Publications by authors named "Henrik Stranneheim"

28 Publications

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High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.

J Hum Genet 2021 Apr 20. Epub 2021 Apr 20.

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.
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http://dx.doi.org/10.1038/s10038-021-00925-xDOI Listing
April 2021

Novel Mutation m.10372A>G in Causing Sensorimotor Axonal Polyneuropathy.

Neurol Genet 2021 Apr 15;7(2):e566. Epub 2021 Mar 15.

Department of Medical Biochemistry and Biophysics (H.B., R.W., C.F., A. Wredenberg), Karolinska Institutet; Centre for Inherited Metabolic Diseases (H.B., R.W., C.F., M.E., N.L., H.S., A. Wedell, A. Wredenberg), Karolinska University Hospital; Department of Clinical Neuroscience (K.S., R.P.), Karolinska Institutet; Department of Neurology (K.S., R.P.), Karolinska University Hospital; Department of Molecular Medicine and Surgery (F.A.S., M.E., N.L., J.C.-G., H.S., A. Wedell), Karolinska Institutet; Department of Pathology (I.N.), Karolinska University Hospital; and Science for Life Laboratory (H.S.), Karolinska Institutet, Stockholm, Sweden.

Objective: To investigate the pathogenicity of a novel mutation identified in a patient with adult-onset sensorimotor axonal polyneuropathy and report the clinical, morphologic, and biochemical findings.

Methods: Clinical assessments and morphologic and biochemical investigations of skeletal muscle and cultured myoblasts from the patient were performed. Whole-genome sequencing (WGS) of DNA from skeletal muscle and Sanger sequencing of mitochondrial DNA (mtDNA) from both skeletal muscle and cultured myoblasts were performed. Heteroplasmic levels of mutated mtDNA in different tissues were quantified by last-cycle hot PCR.

Results: Muscle showed ragged red fibers, paracrystalline inclusions, a significant reduction in complex I (CI) respiratory chain (RC) activity, and decreased adenosine triphosphate (ATP) production for all substrates used by CI. Sanger sequencing of DNA from skeletal muscle detected a unique previously unreported heteroplasmic mutation in mtDNA encoded , coding for a subunit in CI. WGS confirmed the mtDNA mutation but did not detect any other mutation explaining the disease. Cultured myoblasts, however, did not carry the mutation, and RC activity measurements in myoblasts were normal.

Conclusions: We report a case with adult-onset sensorimotor axonal polyneuropathy caused by a novel mtDNA mutation in . Loss of heteroplasmy in blood, cultured fibroblasts and myoblasts from the patient, and normal measurement of RC activity of the myoblasts support pathogenicity of the mutation. These findings highlight the importance of mitochondrial investigations in patients presenting with seemingly idiopathic polyneuropathy, especially if muscle also is affected.
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http://dx.doi.org/10.1212/NXG.0000000000000566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962437PMC
April 2021

Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.

Genome Med 2021 Mar 17;13(1):40. Epub 2021 Mar 17.

Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institutet of Technology, Stockholm, Sweden.

Background: We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting.

Methods: Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout-a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams.

Results: Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange.

Conclusions: Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.
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http://dx.doi.org/10.1186/s13073-021-00855-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968334PMC
March 2021

Severe congenital lactic acidosis and hypertrophic cardiomyopathy caused by an intronic variant in NDUFB7.

Hum Mutat 2021 Apr 4;42(4):378-384. Epub 2021 Feb 4.

Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.

Mutations in structural subunits and assembly factors of complex I of the oxidative phosphorylation system constitute the most common cause of mitochondrial respiratory chain defects. Such mutations can present a wide range of clinical manifestations, varying from mild deficiencies to severe, lethal disorders. We describe a patient presenting intrauterine growth restriction and anemia, which displayed postpartum hypertrophic cardiomyopathy, lactic acidosis, encephalopathy, and a severe complex I defect with fatal outcome. Whole genome sequencing revealed an intronic biallelic mutation in the NDUFB7 gene (c.113-10C>G) and splicing pattern alterations in NDUFB7 messenger RNA were confirmed by RNA Sequencing. The detected variant resulted in a significant reduction of the NDUFB7 protein and reduced complex I activity. Complementation studies with expression of wild-type NDUFB7 in patient fibroblasts normalized complex I function. Here we report a case with a primary complex I defect due to a homozygous mutation in an intron region of the NDUFB7 gene.
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http://dx.doi.org/10.1002/humu.24173DOI Listing
April 2021

Epilepsy syndromes, etiologies, and the use of next-generation sequencing in epilepsy presenting in the first 2 years of life: A population-based study.

Epilepsia 2020 11 23;61(11):2486-2499. Epub 2020 Sep 23.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Objective: Population-based data on epilepsy syndromes and etiologies in early onset epilepsy are scarce. The use of next-generation sequencing (NGS) has hitherto not been reported in this context. The aim of this study is to describe children with epilepsy onset before 2 years of age, and to explore to what degree whole exome and whole genome sequencing (WES/WGS) can help reveal a molecular genetic diagnosis.

Methods: Children presenting with a first unprovoked epileptic seizure before age 2 years and registered in the Stockholm Incidence Registry of Epilepsy (SIRE) between September 1, 2001 and December 31, 2006, were retrieved and their medical records up to age 7 years reviewed. Children who met the epilepsy criteria were included in the study cohort. WES/WGS was offered in cases of suspected genetic etiology regardless of whether a structural or metabolic diagnosis had been established.

Results: One hundred sixteen children were included, of which 88 had seizure onset during the first year of life and 28 during the second, corresponding to incidences of 139 and 42/100 000 person-years, respectively. An epilepsy syndrome could be diagnosed in 54% of cases, corresponding to a birth prevalence of 1/1100. Structural etiology was revealed in 34% of cases, a genetic cause in 20%, and altogether etiology was known in 65% of children. The highest diagnostic yield was seen in magnetic resonance imaging (MRI) with 65% revealing an etiology. WES/WGS was performed in 26/116 cases (22%), with a diagnostic yield of 58%.

Significance: Epilepsy syndromes can be diagnosed and etiologies revealed in a majority of early onset cases. NGS can identify a molecular diagnosis in a substantial number of children, and should be included in the work-up, especially in cases of epileptic encephalopathy, cerebral malformation, or metabolic disease without molecular diagnosis. A genetic diagnosis is essential to genetic counselling, prenatal diagnostics, and precision therapy.
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http://dx.doi.org/10.1111/epi.16701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756847PMC
November 2020

Clinical Presentation, Genetic Etiology, and Coenzyme Q10 Levels in 55 Children with Combined Enzyme Deficiencies of the Mitochondrial Respiratory Chain.

J Pediatr 2021 01 19;228:240-251.e2. Epub 2020 Aug 19.

Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Objectives: To evaluate the clinical symptoms and biochemical findings and establish the genetic etiology in a cohort of pediatric patients with combined deficiencies of the mitochondrial respiratory chain complexes.

Study Design: Clinical and biochemical data were collected from 55 children. All patients were subjected to sequence analysis of the entire mitochondrial genome, except when the causative mutations had been identified based on the clinical picture. Whole exome sequencing/whole genome sequencing (WES/WGS) was performed in 32 patients.

Results: Onset of disease was generally early in life (median age, 6 weeks). The most common symptoms were muscle weakness, hypotonia, and developmental delay/intellectual disability. Nonneurologic symptoms were frequent. Disease causing mutations were found in 20 different nuclear genes, and 7 patients had mutations in mitochondrial DNA. Causative variants were found in 18 of the 32 patients subjected to WES/WGS. Interestingly, many patients had low levels of coenzyme Q10 in muscle, irrespective of genetic cause.

Conclusions: Children with combined enzyme defects display a diversity of clinical symptoms with varying age of presentation. We established the genetic diagnosis in 35 of the 55 patients (64%). The high diagnostic yield was achieved by the introduction of massive parallel sequencing, which also revealed novel genes and enabled elucidation of new disease mechanisms.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.025DOI Listing
January 2021

mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia.

Neurol Genet 2020 Aug 2;6(4):e478. Epub 2020 Jul 2.

Department of Women's and Children's Health (T.S.), Department of Molecular Medicine and Surgery (M.M., N.L., H.S., A. Wedell), Science for Life Laboratory (M.M., H.S., A. Wedell), Department of Medical Biochemistry and Biophysics (A. Wredenberg), and Department of Clinical Neuroscience (D.M.M.), Karolinska Institutet; and Department of Pediatric Neurology (T.S.), Centre for Inherited Metabolic Diseases (N.L., A. Wredenberg, H.S., A. Wedell), and Department of Neuroradiology (D.M.M.), Karolinska University Hospital, Stockholm, Sweden.

Objective: To describe the phenotype in 2 sisters with a rare constellation of neurologic symptoms and secretory impairments and to identify the etiology by the use of whole-genome sequencing (WGS).

Methods: After an extensive workup failed to reveal the cause of disease, in a girl with a previously not reported phenotype, WGS of the proband, her diseased older sister, an older healthy brother, and their parents was performed, and potentially pathogenic variants were analyzed.

Results: The proband and her older sister both presented with neonatal parotitis, apneas, disappearance of the Moro reflex, and hypotonia. The proband survived. Her brain MRI showed white matter and basal ganglia abnormalities, and CSF damage biomarkers were increased. At age 8 years, she exhibits a constellation of symptoms including severe neurodevelopmental disorder, hearing impairment, gastrointestinal problems, and a striking lack of tear fluid, saliva, and sweat. Her respiratory mucosa is dry with potentially life-threatening mucus plugging. Through WGS, 2 loss-of-function variants in were identified that follow an autosomal recessive inheritance pattern.

Conclusions: Taken together with a single previously reported case and the close resemblance to the phenotypes of corresponding mouse models, our study firmly establishes biallelic variants in as causing human disease and adds data regarding the neurologic phenotype.
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http://dx.doi.org/10.1212/NXG.0000000000000478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357422PMC
August 2020

Loqusdb: added value of an observations database of local genomic variation.

BMC Bioinformatics 2020 Jul 1;21(1):273. Epub 2020 Jul 1.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Background: Exome and genome sequencing is becoming the method of choice for rare disease diagnostics. One of the key challenges remaining is distinguishing the disease causing variants from the benign background variation. After analysis and annotation of the sequencing data there are typically thousands of candidate variants requiring further investigation. One of the most effective and least biased ways to reduce this number is to assess the rarity of a variant in any population. Currently, there are a number of reliable sources of information for major population frequencies when considering single nucleotide variants (SNVs) and small insertion and deletions (INDELs), with gnomAD as the most prominent public resource available. However, local variation or frequencies in sub-populations may be underrepresented in these public resources. In contrast, for structural variation (SV), the background frequency in the general population is more or less unknown mostly due to challenges in calling SVs in a consistent way. Keeping track of local variation is one way to overcome these problems and significantly reduce the number of potential disease causing variants retained for manual inspection, both for SNVs and SVs.

Results: Here, we present loqusdb, a tool to solve the challenge of keeping track of any type of variant observations from genome sequencing data. Loqusdb was designed to handle a large flow of samples and unlike other solutions, samples can be added continuously to the database without rebuilding it, facilitating improvements and additions. We assessed the added value of a local observations database using 98 samples annotated with information from a background of 888 unrelated individuals.

Conclusions: We show both how powerful SV analysis can be when filtering for population frequencies and how the number of apparently rare SNVs/INDELs can be reduced by adding local population information even after annotating the data with other large frequency databases, such as gnomAD. In conclusion, we show that a local frequency database is an attractive, and a necessary addition to the publicly available databases that facilitate the analysis of exome and genome data in a clinical setting.
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http://dx.doi.org/10.1186/s12859-020-03609-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329469PMC
July 2020

From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability.

Genome Med 2019 11 7;11(1):68. Epub 2019 Nov 7.

Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Background: Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.

Methods: We analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n = 68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n = 156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.

Results: First, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850 kb (min 500 bp, max 155 Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (> 10 kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data. Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.

Conclusion: The overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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http://dx.doi.org/10.1186/s13073-019-0675-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836550PMC
November 2019

SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation.

Stem Cell Reports 2019 04 28;12(4):696-711. Epub 2019 Feb 28.

Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, 171 65 Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden. Electronic address:

Neurodegenerative disorders are an increasingly common and irreversible burden on society, often affecting the aging population, but their etiology and disease mechanisms are poorly understood. Studying monogenic neurodegenerative diseases with known genetic cause provides an opportunity to understand cellular mechanisms also affected in more complex disorders. We recently reported that loss-of-function mutations in the autophagy adaptor protein SQSTM1/p62 lead to a slowly progressive neurodegenerative disease presenting in childhood. To further elucidate the neuronal involvement, we studied the cellular consequences of loss of p62 in a neuroepithelial stem cell (NESC) model and differentiated neurons derived from reprogrammed p62 patient cells or by CRISPR/Cas9-directed gene editing in NESCs. Transcriptomic and proteomic analyses suggest that p62 is essential for neuronal differentiation by controlling the metabolic shift from aerobic glycolysis to oxidative phosphorylation required for neuronal maturation. This shift is blocked by the failure to sufficiently downregulate lactate dehydrogenase expression due to the loss of p62, possibly through impaired Hif-1α downregulation and increased sensitivity to oxidative stress. The findings imply an important role for p62 in neuronal energy metabolism and particularly in the regulation of the shift between glycolysis and oxidative phosphorylation required for normal neurodifferentiation.
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http://dx.doi.org/10.1016/j.stemcr.2019.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449840PMC
April 2019

Chorea, psychosis, acanthocytosis, and prolonged survival associated with mutations.

Neurology 2018 10 14;91(15):710-712. Epub 2018 Sep 14.

From Karolinska University Hospital (M.P., A.P., C.F., M.D., J.L.-M., H.S., K.L., I.S., A. Wedell, A. Wredenberg, P.S.); Karolinska Institutet (M.P., A.P., C.F., Å.B., K.L., A. Wedell, A. Wredenberg, P.S.), Stockholm, Sweden; James J. Peters Veterans Medical Affair Center (R.H.W.), Bronx; and Mount Sinai School of Medicine (R.H.W.), New York, NY.

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http://dx.doi.org/10.1212/WNL.0000000000006320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177277PMC
October 2018

Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model.

Orphanet J Rare Dis 2017 04 20;12(1):73. Epub 2017 Apr 20.

Division of Pediatrics, Department of Clinical Sciences, Lund University, 221 84, Lund, Sweden.

Background: Mitochondrial diseases due to defective respiratory chain complex III (CIII) are relatively uncommon. The assembly of the eleven-subunit CIII is completed by the insertion of the Rieske iron-sulfur protein, a process for which BCS1L protein is indispensable. Mutations in the BCS1L gene constitute the most common diagnosed cause of CIII deficiency, and the phenotypic spectrum arising from mutations in this gene is wide.

Results: A case of CIII deficiency was investigated in depth to assess respiratory chain function and assembly, and brain, skeletal muscle and liver histology. Exome sequencing was performed to search for the causative mutation(s). The patient's platelets and muscle mitochondria showed respiration defects and defective assembly of CIII was detected in fibroblast mitochondria. The patient was compound heterozygous for two novel mutations in BCS1L, c.306A > T and c.399delA. In the cerebral cortex a specific pattern of astrogliosis and widespread loss of microglia was observed. Further analysis showed loss of Kupffer cells in the liver. These changes were not found in infants suffering from GRACILE syndrome, the most severe BCS1L-related disorder causing early postnatal mortality, but were partially corroborated in a knock-in mouse model of BCS1L deficiency.

Conclusions: We describe two novel compound heterozygous mutations in BCS1L causing CIII deficiency. The pathogenicity of one of the mutations was unexpected and points to the importance of combining next generation sequencing with a biochemical approach when investigating these patients. We further show novel manifestations in brain, skeletal muscle and liver, including abnormality in specialized resident macrophages (microglia and Kupffer cells). These novel phenotypes forward our understanding of CIII deficiencies caused by BCS1L mutations.
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http://dx.doi.org/10.1186/s13023-017-0624-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399415PMC
April 2017

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.

Am J Hum Genet 2016 09 18;99(3):735-743. Epub 2016 Aug 18.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.

SQSTM1 (sequestosome 1; also known as p62) encodes a multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor. Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using exome sequencing, we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation. Our findings expand the SQSTM1-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010644PMC
September 2016

Biotin and Thiamine Responsive Basal Ganglia Disease--A vital differential diagnosis in infants with severe encephalopathy.

Eur J Paediatr Neurol 2016 May 4;20(3):457-61. Epub 2016 Feb 4.

Neuropediatric Unit, Dept of Women's and Children's Health, Karolinska Institutet, Sweden.

Unlabelled: We report two siblings of Swedish origin with infantile Biotin and Thiamine Responsive Basal Ganglia Disease (BTRBG).

Case Report: Initial symptoms were in both cases lethargia, with reduced contact and poor feeding from the age of 5 weeks. Magnetic resonance imaging showed altered signal in the basal ganglia, along with grey and white matter abnormalities. The diagnosis BTRBG was not recognized in the first sibling who died at the age of 8 weeks. The second sibling was started on biotin and thiamine immediately upon development of symptoms, leading to clinical improvement and partial reversion of the magnetic resonance imaging findings. Genetic analysis of the SLC19A3 gene identified two mutations, c.74dupT and c.1403delA, carried in compound heterozygous form in both boys, each inherited from one parent.

Comments: The first mutation has previously been described in children with BTRBG, and the second mutation is novel. Although the clinical picture in BTRGB is very severe it is also rather unspecific and the diagnosis may be missed.

Conclusion: This report highlights the importance of considering biotin and thiamine treatment also in a European infant born to non-consanguineous parents, who presents with symptoms of acute/subacute encephalopathy.
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http://dx.doi.org/10.1016/j.ejpn.2016.01.009DOI Listing
May 2016

Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26.

Am J Hum Genet 2015 Nov 29;97(5):761-8. Epub 2015 Oct 29.

Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Science for Life Laboratory and Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.

S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.
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http://dx.doi.org/10.1016/j.ajhg.2015.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667130PMC
November 2015

Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.

Nat Commun 2015 Sep 3;6:8038. Epub 2015 Sep 3.

Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK.

The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy.
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http://dx.doi.org/10.1038/ncomms9038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569694PMC
September 2015

Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid.

J Med Genet 2015 Nov 17;52(11):779-83. Epub 2015 Jun 17.

Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.

Background: Coenzyme Q is an essential mitochondrial electron carrier, redox cofactor and a potent antioxidant in the majority of cellular membranes. Coenzyme Q deficiency has been associated with a range of metabolic diseases, as well as with some drug treatments and ageing.

Methods: We used whole exome sequencing (WES) to investigate patients with inherited metabolic diseases and applied a novel ultra-pressure liquid chromatography-mass spectrometry approach to measure coenzyme Q in patient samples.

Results: We identified a homozygous missense mutation in the COQ7 gene in a patient with complex mitochondrial deficiency, resulting in severely reduced coenzyme Q levels We demonstrate that the coenzyme Q analogue 2,4-dihydroxybensoic acid (2,4DHB) was able to specifically bypass the COQ7 deficiency, increase cellular coenzyme Q levels and rescue the biochemical defect in patient fibroblasts.

Conclusion: We report the first patient with primary coenzyme Q deficiency due to a homozygous COQ7 mutation and a potentially beneficial treatment using 2,4DHB.
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http://dx.doi.org/10.1136/jmedgenet-2015-102986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680133PMC
November 2015

Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism.

BMC Genomics 2014 Dec 11;15:1090. Epub 2014 Dec 11.

Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine.

Results: We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in-house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome.

Conclusions: We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent.
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http://dx.doi.org/10.1186/1471-2164-15-1090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299811PMC
December 2014

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge.

Genome Biol 2014 Mar 25;15(3):R53. Epub 2014 Mar 25.

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.

Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization.

Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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http://dx.doi.org/10.1186/gb-2014-15-3-r53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073084PMC
March 2014

Comparison of total and cytoplasmic mRNA reveals global regulation by nuclear retention and miRNAs.

BMC Genomics 2012 Oct 30;13:574. Epub 2012 Oct 30.

KTH Royal Institute of Technology, Science for Life Laboratory (SciLifeLab Stockholm), School of Biotechnology, Division of Gene Technology, SE-171 65, Solna, Sweden.

Background: The majority of published gene-expression studies have used RNA isolated from whole cells, overlooking the potential impact of including nuclear transcriptome in the analyses. In this study, mRNA fractions from the cytoplasm and from whole cells (total RNA) were prepared from three human cell lines and sequenced using massive parallel sequencing.

Results: For all three cell lines, of about 15000 detected genes approximately 400 to 1400 genes were detected in different amounts in the cytoplasmic and total RNA fractions. Transcripts detected at higher levels in the total RNA fraction had longer coding sequences and higher number of miRNA target sites. Transcripts detected at higher levels in the cytoplasmic fraction were shorter or contained shorter untranslated regions. Nuclear retention of transcripts and mRNA degradation via miRNA pathway might contribute to this differential detection of genes. The consequence of the differential detection was further investigated by comparison to proteomics data. Interestingly, the expression profiles of cytoplasmic and total RNA correlated equally well with protein abundance levels indicating regulation at a higher level.

Conclusions: We conclude that expression levels derived from the total RNA fraction be regarded as an appropriate estimate of the amount of mRNAs present in a given cell population, independent of the coding sequence length or UTRs.
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http://dx.doi.org/10.1186/1471-2164-13-574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495644PMC
October 2012

Gene expression profiles in paired gingival biopsies from periodontitis-affected and healthy tissues revealed by massively parallel sequencing.

PLoS One 2012 28;7(9):e46440. Epub 2012 Sep 28.

Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.

Periodontitis is a chronic inflammatory disease affecting the soft tissue and bone that surrounds the teeth. Despite extensive research, distinctive genes responsible for the disease have not been identified. The objective of this study was to elucidate transcriptome changes in periodontitis, by investigating gene expression profiles in gingival tissue obtained from periodontitis-affected and healthy gingiva from the same patient, using RNA-sequencing. Gingival biopsies were obtained from a disease-affected and a healthy site from each of 10 individuals diagnosed with periodontitis. Enrichment analysis performed among uniquely expressed genes for the periodontitis-affected and healthy tissues revealed several regulated pathways indicative of inflammation for the periodontitis-affected condition. Hierarchical clustering of the sequenced biopsies demonstrated clustering according to the degree of inflammation, as observed histologically in the biopsies, rather than clustering at the individual level. Among the top 50 upregulated genes in periodontitis-affected tissues, we investigated two genes which have not previously been demonstrated to be involved in periodontitis. These included interferon regulatory factor 4 and chemokine (C-C motif) ligand 18, which were also expressed at the protein level in gingival biopsies from patients with periodontitis. In conclusion, this study provides a first step towards a quantitative comprehensive insight into the transcriptome changes in periodontitis. We demonstrate for the first time site-specific local variation in gene expression profiles of periodontitis-affected and healthy tissues obtained from patients with periodontitis, using RNA-seq. Further, we have identified novel genes expressed in periodontitis tissues, which may constitute potential therapeutic targets for future treatment strategies of periodontitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046440PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460903PMC
February 2013

Stepping stones in DNA sequencing.

Biotechnol J 2012 Sep 8;7(9):1063-73. Epub 2012 Aug 8.

Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.

In recent years there have been tremendous advances in our ability to rapidly and cost-effectively sequence DNA. This has revolutionized the fields of genetics and biology, leading to a deeper understanding of the molecular events in life processes. The rapid technological advances have enormously expanded sequencing opportunities and applications, but also imposed strains and challenges on steps prior to sequencing and in the downstream process of handling and analysis of these massive amounts of sequence data. Traditionally, sequencing has been limited to small DNA fragments of approximately one thousand bases (derived from the organism's genome) due to issues in maintaining a high sequence quality and accuracy for longer read lengths. Although many technological breakthroughs have been made, currently the commercially available massively parallel sequencing methods have not been able to resolve this issue. However, recent announcements in nanopore sequencing hold the promise of removing this read-length limitation, enabling sequencing of larger intact DNA fragments. The ability to sequence longer intact DNA with high accuracy is a major stepping stone towards greatly simplifying the downstream analysis and increasing the power of sequencing compared to today. This review covers some of the technical advances in sequencing that have opened up new frontiers in genomics.
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http://dx.doi.org/10.1002/biot.201200153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472021PMC
September 2012

Scalable transcriptome preparation for massive parallel sequencing.

PLoS One 2011 7;6(7):e21910. Epub 2011 Jul 7.

Science for Life Laboratory, Division of Gene Technology, School of Biotechnology, Royal Institute of Technology (KTH), Solna, Sweden.

Background: The tremendous output of massive parallel sequencing technologies requires automated robust and scalable sample preparation methods to fully exploit the new sequence capacity.

Methodology: In this study, a method for automated library preparation of RNA prior to massively parallel sequencing is presented. The automated protocol uses precipitation onto carboxylic acid paramagnetic beads for purification and size selection of both RNA and DNA. The automated sample preparation was compared to the standard manual sample preparation.

Conclusion/significance: The automated procedure was used to generate libraries for gene expression profiling on the Illumina HiSeq 2000 platform with the capacity of 12 samples per preparation with a significantly improved throughput compared to the standard manual preparation. The data analysis shows consistent gene expression profiles in terms of sensitivity and quantification of gene expression between the two library preparation methods.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021910PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131396PMC
October 2011

Sun-induced nonsynonymous p53 mutations are extensively accumulated and tolerated in normal appearing human skin.

J Invest Dermatol 2011 Feb 14;131(2):504-8. Epub 2010 Oct 14.

Division of Gene Technology, Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden.

Here we demonstrate that intermittently sun-exposed human skin contains an extensive number of phenotypically intact cell compartments bearing missense and nonsense mutations in the p53 tumor suppressor gene. Deep sequencing of sun-exposed and shielded microdissected skin from mid-life individuals revealed that persistent p53 mutations had accumulated in 14% of all epidermal cells, with no apparent signs of a growth advantage of the affected cell compartments. Furthermore, 6% of the mutated epidermal cells encoded a truncated protein. The abundance of these events, not taking into account intron mutations and mutations in other genes that also may have functional implications, suggests an extensive tolerance of human cells to severe genetic alterations caused by UV light, with an estimated annual rate of accumulation of ∼35,000 new persistent protein-altering p53 mutations in sun-exposed skin of a human individual.
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http://dx.doi.org/10.1038/jid.2010.302DOI Listing
February 2011

Classification of DNA sequences using Bloom filters.

Bioinformatics 2010 Jul 13;26(13):1595-600. Epub 2010 May 13.

Science for Life Laboratory, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden.

Motivation: New generation sequencing technologies producing increasingly complex datasets demand new efficient and specialized sequence analysis algorithms. Often, it is only the 'novel' sequences in a complex dataset that are of interest and the superfluous sequences need to be removed.

Results: A novel algorithm, fast and accurate classification of sequences (FACSs), is introduced that can accurately and rapidly classify sequences as belonging or not belonging to a reference sequence. FACS was first optimized and validated using a synthetic metagenome dataset. An experimental metagenome dataset was then used to show that FACS achieves comparable accuracy as BLAT and SSAHA2 but is at least 21 times faster in classifying sequences.

Availability: Source code for FACS, Bloom filters and MetaSim dataset used is available at http://facs.biotech.kth.se. The Bloom::Faster 1.6 Perl module can be downloaded from CPAN at http://search.cpan.org/ approximately palvaro/Bloom-Faster-1.6/

Contacts: [email protected]; [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btq230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887045PMC
July 2010

Increased throughput by parallelization of library preparation for massive sequencing.

PLoS One 2010 Apr 6;5(4):e10029. Epub 2010 Apr 6.

Division of Gene Technology, School of Biotechnology, Royal Institute of Technology (KTH), Stockholm, Sweden.

Background: Massively parallel sequencing systems continue to improve on data output, while leaving labor-intensive library preparations a potential bottleneck. Efforts are currently under way to relieve the crucial and time-consuming work to prepare DNA for high-throughput sequencing.

Methodology/principal Findings: In this study, we demonstrate an automated parallel library preparation protocol using generic carboxylic acid-coated superparamagnetic beads and polyethylene glycol precipitation as a reproducible and flexible method for DNA fragment length separation. With this approach the library preparation for DNA sequencing can easily be adjusted to a desired fragment length. The automated protocol, here demonstrated using the GS FLX Titanium instrument, was compared to the standard manual library preparation, showing higher yield, throughput and great reproducibility. In addition, 12 libraries were prepared and uniquely tagged in parallel, and the distribution of sequence reads between these indexed samples could be improved using quantitative PCR-assisted pooling.

Conclusions/significance: We present a novel automated procedure that makes it possible to prepare 36 indexed libraries per person and day, which can be increased to up to 96 libraries processed simultaneously. The yield, speed and robust performance of the protocol constitute a substantial improvement to present manual methods, without the need of extensive equipment investments. The described procedure enables a considerable efficiency increase for small to midsize sequencing centers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0010029PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850305PMC
April 2010

A comparison between protein profiles of B cell subpopulations and mantle cell lymphoma cells.

Proteome Sci 2009 Nov 23;7:43. Epub 2009 Nov 23.

Department of Gene Technology, AlbaNova University Center, Royal Institute of Technology, Stockholm, Sweden.

Background: B-cell lymphomas are thought to reflect different stages of B-cell maturation. Based on cytogenetics and molecular markers, mantle cell lymphoma (MCL) is presumed to derive predominantly from naïve, pre-germinal centre (pre-GC) B lymphocytes. The aim of this study was to develop a method to investigate the similarity between MCL cells and different B-cell compartments on a protein expression level.

Methods: Subpopulations of B cells representing the germinal centre (GC), the pre-GC mantle zone and the post-GC marginal zone were isolated from tonsils using automated magnetic cell sorting (AutoMACS) of cells based on their expression of CD27 and IgD. Protein profiling of the B cell subsets, of cell lines representing different lymphomas and of primary MCL samples was performed using top-down proteomics profiling by surface-enhanced laser detection/ionization time-of-flight mass spectrometry (SELDI-TOF-MS).

Results: Quantitative MS data of significant protein peaks (p-value < 0.05) separating the three B-cell subpopulations were generated. Together, hierarchical clustering and principal component analysis (PCA) showed that the primary MCL samples clustered together with the pre- and post-GC subpopulations. Both primary MCL cells and MCL cell lines were clearly separated from the B cells representing the GC compartment.

Conclusion: AutoMACS sorting generates sufficient purity to enable a comparison between protein profiles of B cell subpopulations and malignant B lymphocytes applying SELDI-TOF-MS. Further validation with an increased number of patient samples and identification of differentially expressed proteins would enable a search for possible treatment targets that are expressed during the early development of MCL.
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http://dx.doi.org/10.1186/1477-5956-7-43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789720PMC
November 2009

Inheritance of acquired behaviour adaptations and brain gene expression in chickens.

PLoS One 2009 Jul 28;4(7):e6405. Epub 2009 Jul 28.

IFM Biology Division of Zoology, Linköping University Sweden, Linköping, Sweden.

Background: Environmental challenges may affect both the exposed individuals and their offspring. We investigated possible adaptive aspects of such cross-generation transmissions, and hypothesized that chronic unpredictable food access would cause chickens to show a more conservative feeding strategy and to be more dominant, and that these adaptations would be transmitted to the offspring.

Methodology/principal Findings: Parents were raised in an unpredictable (UL) or in predictable diurnal light rhythm (PL, 12:12 h light:dark). In a foraging test, UL birds pecked more at freely available, rather than at hidden and more attractive food, compared to birds from the PL group. Female offspring of UL birds, raised in predictable light conditions without parental contact, showed a similar foraging behavior, differing from offspring of PL birds. Furthermore, adult offspring of UL birds performed more food pecks in a dominance test, showed a higher preference for high energy food, survived better, and were heavier than offspring of PL parents. Using cDNA microarrays, we found that the differential brain gene expression caused by the challenge was mirrored in the offspring. In particular, several immunoglobulin genes seemed to be affected similarly in both UL parents and their offspring. Estradiol levels were significantly higher in egg yolk from UL birds, suggesting one possible mechanism for these effects.

Conclusions/significance: Our findings suggest that unpredictable food access caused seemingly adaptive responses in feeding behavior, which may have been transmitted to the offspring by means of epigenetic mechanisms, including regulation of immune genes. This may have prepared the offspring for coping with an unpredictable environment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006405PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713434PMC
July 2009
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