Publications by authors named "Baiba Lace"

37 Publications

A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy.

Front Neurol 2021 15;12:660113. Epub 2021 Jun 15.

Centre de recherche CHU de Québec- Laval University, Quebec City, QC, Canada.

Nemaline myopathy is a rare disorder affecting the muscle sarcomere. Mutations in nebulin gene () are known to be responsible for about 50% of nemaline myopathy cases. Nebulin is a giant protein which is formed integrally with the sarcomeric thin filament. This complex gene is under extensive alternative splicing giving rise to multiple isoforms. In this study, we report a 6-year-old boy presenting with general muscular weaknesses. Identification of rod-shaped structures in the patient' biopsy raised doubt about the presence of a nemaline myopathy. Next-generation sequencing was used to identify a causative mutation for the patient syndrome. A homozygous deep intronic substitution was found in the intron 144 of the . The variant was predicted by tools to create a new donor splice site. Molecular analysis has shown that the mutation could alter splicing events of the nebulin gene leading to a significant decrease of isoforms level. This change in the expression level of nebulin could give rise to functional consequences in the sarcomere. These results are consistent with the phenotypes observed in the patient. Such a discovery of variants in this gene will allow a better understanding of the involvement of nebulin in neuromuscular diseases and help find new treatments for the nemaline myopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2021.660113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239344PMC
June 2021

Differences in Leaf Morphological Parameters of Pear ( L.) Based on Their Susceptibility to European Pear Rust Caused by (Dicks.) Oerst.

Plants (Basel) 2021 May 20;10(5). Epub 2021 May 20.

Institute of Horticulture, Graudu 1, LV-3701 Dobele, Latvia.

European pear rust is an important disease; however, the relationship between its causal pathogen (Dicks.) Oerst. and host L. is poorly understood. In this study, disease severity was measured, and leaf samples were collected over three years, and their leaf water content; leaf area; leaf mass per area; and epidermis, mesophyll, and vascular tissue width and stomatal density were measured and compared between susceptible and resistant genotypes for each year. Most genotypes either showed consistent disease symptoms or showed no symptoms during the study in terms of their susceptibility. A correlation between disease severity and mesophyll tissue thickness, and stomatal density and differences between several morphological parameters were found depending on the genotype's susceptibility. The study showed that the following pear morphological traits were stable between the years: water content, leaf mass per area, spongy mesophyll thickness, phloem thickness, and stomatal density. When selecting for breeding, we found that candidates for traits that discern susceptible genotypes from resistant were mesophyll layer width, stomatal density, epidermis width, and xylem tissue width.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/plants10051024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161175PMC
May 2021

A founder mutation in the gene in families from Saguenay-Lac-St-Jean region affected by a pyridoxine-dependent epilepsy.

JIMD Rep 2021 May 23;59(1):32-41. Epub 2021 Feb 23.

Centre de recherche CHU de Québec- Université Laval, Laval University Québec Québec Canada.

Pyridoxine-dependent epilepsy (PDE) is a relatively rare subgroup of epileptic disorders. They generally present in infancy as an early onset epileptic encephalopathy or seizures, refractory to standard treatments, with rapid and variable responses to vitamin B6 treatment. Whole exome sequencing of three unrelated families identified homozygous pathogenic mutation c.370_373del, p.Asp124fs in gene in five persons. Haplotype analysis showed a single shared profile for the affected persons and their parents, leading to a hypothesis about founder effect of the mutation in Saguenay-Lac-St-Jean region of French Canadians. All affected probands also shared one single mitochondrial haplotype T2b3 and two rare variations in the mitochondrial genome m.801A>G and m.5166A>G suggesting that a single individual female introduced mutation c.370_373del, p.Asp124fs in Quebec. The mutation p.Asp124fs causes a severe disease phenotype with delayed myelination and cortical/subcortical brain atrophy. The most noteworthy radiological finding in this Quebec founder mutation is the presence of the temporal cysts that can be used as a marker of the disease. Also, both patients, who are alive, had a history of prenatal supplements taken by their mothers as antiemetic medication with high doses of pyridoxine. In the context of suspected PDE in patients with neonatal refractory seizures, treatment with pyridoxine and/or Pyridoxal-5-phophate has to be started immediately and continued until the results of genetic analysis received. Even with early appropriate treatment, neurological outcome of our patient is still poor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmd2.12196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100403PMC
May 2021

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia.

Ann Neurol 2021 03 15;89(3):485-497. Epub 2020 Dec 15.

Ken and Ruth Davee Department of Neurology and Simpson Querry Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.

Objective: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia.

Methods: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients.

Results: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia.

Interpretation: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986743PMC
March 2021

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.

Eur J Hum Genet 2020 10 1;28(10):1422-1431. Epub 2020 Jun 1.

Clinical Geneticist Medical Genetics Department, CHUQ-CHUL, Quebec, Canada.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-020-0654-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608102PMC
October 2020

Collagen VI-related limb-girdle syndrome caused by frequent mutation in COL6A3 gene with conflicting reports of pathogenicity.

Neuromuscul Disord 2020 06 18;30(6):483-491. Epub 2020 Apr 18.

Latvian Biomedical Research and Study Centre, Ratsupites 1, Riga LV-1067, Latvia; Medical Genetics department, CHUQ, 2705 Blvd Laurier, Quebec City, Canada.

Recently the scientific community has started to view Bethlem myopathy 1 and Ullrich congenital muscular dystrophy as two extremes of a collagen VI-related myopathy spectrum rather than two separate entities, as both are caused by mutations in one of the collagen VI genes. Here we report three individuals in two families who are homozygous for a COL6A3 mutation (c.7447A> G; p.Lys2483Glu), and compare their clinical features with seven previously published cases. Individuals carrying homozygous or compound heterozygous c.7447A> G, (p.Lys2483Glu) mutation exhibit mild phenotype without loss of ambulation, similar to the cases described previously as Collagen VI-related limb-girdle syndrome. The phenotype could arise due to an aberrant assembly of Von Willebrand factor A domains. Based on these data, we propose that c.7447A> G, (p.Lys2483Glu) is a common pathogenic mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2020.03.010DOI Listing
June 2020

Whole-exome sequencing identifies homozygous mutation in TTI2 in a child with primary microcephaly: a case report.

BMC Neurol 2020 Feb 15;20(1):58. Epub 2020 Feb 15.

Department of Paediatric Neurology, Paediatric Neuromuscular Disorder, Centre Mère Enfant Soleil, Laval University, Québec, Qc, Canada.

Background: Primary microcephaly is defined as reduced occipital-frontal circumference noticeable before 36 weeks of gestation. Large amount of insults might lead to microcephaly including infections, hypoxia and genetic mutations. More than 16 genes are described in autosomal recessive primary microcephaly. However, the cause of microcephaly remains unclear in many cases after extensive investigations and genetic screening.

Case Presentation: Here, we described the case of a boy with primary microcephaly who presented to a neurology clinic with short stature, global development delay, dyskinetic movement, strabismus and dysmorphic features. We performed microcephaly investigations and genetic panels. Then, we performed whole-exome sequencing to identify any genetic cause. Microcephaly investigations and genetic panels were negative, but we found a new D317V homozygous mutation in TELOE-2 interacting protein 2 (TTI2) gene by whole-exome sequencing. TTI2 is implicated in DNA damage response and mutation in that gene was previously described in mental retardation, autosomal recessive 39.

Conclusions: We described the first French Canadian case with primary microcephaly and global developmental delay secondary to a new D317V homozygous mutation in TTI2 gene. Our report also highlights the importance of TTI2 protein in brain development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-020-01643-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023720PMC
February 2020

HSD10 mitochondrial disease: p.Leu122Val variant, mild clinical phenotype, and founder effect in French-Canadian patients from Quebec.

Mol Genet Genomic Med 2019 12 26;7(12):e1000. Epub 2019 Oct 26.

Medical Genetics, Department of Pediatrics, Université de Sherbrooke-CHUS, Sherbrooke, QC, Canada.

Background: HSD10 mitochondrial disease (HSD10MD), originally described as a deficiency of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD), is a rare X-linked disorder of a moonlighting protein encoded by the HSD17B10. The diagnosis is usually first suspected on finding elevated isoleucine degradation metabolites in urine, reflecting decreased MHBD activity. However, it is now known that clinical disease pathogenesis reflects other independent functions of the HSD10 protein; particularly its essential role in mitochondrial transcript processing and tRNA maturation. The classical phenotype of HSD10MD in affected males is an infantile-onset progressive neurodegenerative disorder associated with severe mitochondrial dysfunction.

Patients, Methods, And Results: In four unrelated families, we identified index patients with MHBD deficiency, which implied a diagnosis of HSD10MD. Each index patient was independently investigated because of neurological or developmental concerns. All had persistent elevations of urinary 2-methyl-3-hydroxybutyric acid and tiglylglycine. Analysis of HSD17B10 identified a single missense variant, c.364C>G, p.Leu122Val, in each case. This rare variant (1/183336 alleles in gnomAD) was previously reported in one Dutch patient and was described as pathogenic. The geographic origins of our families and results of haplotype analysis together provide evidence of a founder effect for this variant in Quebec. Notably, we identified an asymptomatic hemizygous adult male in one family, while a second independent genetic disorder contributed substantially to the clinical phenotypes observed in probands from two other families.

Conclusion: The phenotype associated with p.Leu122Val in HSD17B10 currently appears to be attenuated and nonprogressive. This report widens the spectrum of phenotypic severity of HSD10MD and contributes to genotype-phenotype correlation. At present, we consider p.Leu122Val a "variant of uncertain significance." Nonetheless, careful follow-up of our patients remains advisable, to assess long-term clinical course and ensure appropriate management. It will also be important to identify other potential patients in our population and to characterize their phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900358PMC
December 2019

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Am J Hum Genet 2019 08 27;105(2):384-394. Epub 2019 Jun 27.

Department of Paediatric Neurology, Leicester Royal Infirmary, Leicester LE1 5WW, UK.

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698938PMC
August 2019

Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy.

Ann Neurol 2019 07 17;86(1):129-142. Epub 2019 May 17.

Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.

Objective: To define a distinct, dominantly inherited, mild skeletal myopathy associated with prominent and consistent tremor in two unrelated, three-generation families.

Methods: Clinical evaluations as well as exome and panel sequencing analyses were performed in affected and nonaffected members of two families to identify genetic variants segregating with the phenotype. Histological assessment of a muscle biopsy specimen was performed in 1 patient, and quantitative tremor analysis was carried out in 2 patients. Molecular modeling studies and biochemical assays were performed for both mutations.

Results: Two novel missense mutations in MYBPC1 (p.E248K in family 1 and p.Y247H in family 2) were identified and shown to segregate perfectly with the myopathy/tremor phenotype in the respective families. MYBPC1 encodes slow myosin binding protein-C (sMyBP-C), a modular sarcomeric protein playing structural and regulatory roles through its dynamic interaction with actin and myosin filaments. The Y247H and E248K mutations are located in the NH -terminal M-motif of sMyBP-C. Both mutations result in markedly increased binding of the NH terminus to myosin, possibly interfering with normal cross-bridge cycling as the first muscle-based step in tremor genesis. The clinical tremor features observed in all mutation carriers, together with the tremor physiology studies performed in family 2, suggest amplification by an additional central loop modulating the clinical tremor phenomenology.

Interpretation: Here, we link two novel missense mutations in MYBPC1 with a dominant, mild skeletal myopathy invariably associated with a distinctive tremor. The molecular, genetic, and clinical studies are consistent with a unique sarcomeric origin of the tremor, which we classify as "myogenic tremor." ANN NEUROL 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685440PMC
July 2019

Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients.

Int J Mol Sci 2018 Mar 28;19(4). Epub 2018 Mar 28.

Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mitochondrial HMG-CoA synthase deficiency or mHS deficiency, OMIM #605911) is an inborn error of metabolism that affects ketone body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycemia and dicarboxylic aciduria. The diagnosis is difficult due to the relatively unspecific clinical and biochemical presentation, and fewer than 30 patients have been described. This work describes three new patients with mHS deficiency and two missense mutations c.334C>T (p.R112W) and c.430G>T (p.V144L) previously not reported. We developed a new method to express and measure the activity of the enzyme and in this work the study is extended to ten new missense variants including those of our patients. Enzymatic assays showed that three of the mutant proteins retained some but seven completely lacked activity. The identification of a patient homozygous for a mutation that retains 70% of enzyme activity opens the door to a new interpretation of the disease by demonstrating that a modest impairment of enzyme function can actually produce symptoms. This is also the first study employing molecular dynamics modelling of the enzyme mutations. We show that the correct maintenance of the dimerization surface is crucial for retaining the structure of the active center and therefore the activity of the enzyme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms19041010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979369PMC
March 2018

Complete mtDNA sequencing reveals mutations m.9185T>C and m.13513G>A in three patients with Leigh syndrome.

Mitochondrial DNA A DNA Mapp Seq Anal 2018 10 12;29(7):1115-1120. Epub 2017 Dec 12.

a Latvian Biomedical Research and Study Centre , Riga , Latvia.

The most common mitochondrial disorder in children is Leigh syndrome, which is a progressive and genetically heterogeneous neurodegenerative disorder caused by mutations in nuclear genes or mitochondrial DNA (mtDNA). In the present study, a novel and robust method of complete mtDNA sequencing, which allows amplification of the whole mitochondrial genome, was tested. Complete mtDNA sequencing was performed in a cohort of patients with suspected mitochondrial mutations. Patients from Latvia and Lithuania (n = 92 and n = 57, respectively) referred by clinical geneticists were included. The de novo point mutations m.9185T>C and m.13513G>A, respectively, were detected in two patients with lactic acidosis and neurodegenerative lesions. In one patient with neurodegenerative lesions, the mutation m.9185T>C was identified. These mutations are associated with Leigh syndrome. The present data suggest that full-length mtDNA sequencing is recommended as a supplement to nuclear gene testing and enzymatic assays to enhance mitochondrial disease diagnostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/24701394.2017.1413365DOI Listing
October 2018

A New Baltic Population-Specific Human Genetic Marker in the PMCA4 Gene.

Hum Hered 2016 2;82(3-4):140-146. Epub 2017 Nov 2.

Latvian Biomedical Research and Study Centre, Riga, Latvia.

Objectives: The PMCA gene family consists of 4 genes and at least 21 splice variants; among these, the Ca2+ ATPase 4 (PMCA4) gene encodes a plasma membrane protein abundantly expressed in several tissues, including the kidney, heart, and sperm. Knockout of PMCA4 causes infertility due to immotile sperm in mouse models. We therefore investigated variants in this gene for potential association with infertility in groups of Estonian (n = 191) and Latvian (n = 92) men with reduced sperm motility.

Methods: All exons, exon-intron boundaries, 5' and 3' untranslated regions, and the promoter region of the PMCA4 gene were analysed by direct sequencing for a group of Estonian infertile men. Genotyping of guanine and adenine alleles of rs147729934 was performed, using a custom-designed TaqMan® probe for a group of Latvian infertile men as well as additional groups from Latvia and several groups of people with proven ethnicity from the Baltic region.

Results: Although we did not identify any significant associations between variants in the gene and infertility, our results indicated that in all studied Latvian and Estonian groups the adenine allele of the variant rs147729934 was present at a higher frequency than expected. Analysis of additional samples indicated that the adenine allele of rs147729934 likely originated once in the modern-day Baltic or western Russia area, as the frequency of the minor adenine allele observed in this region is remarkably higher than that in the general European population.

Conclusions: Our results revealed no significant difference in frequencies of genetic variants in PMCA4 gene between men with normal and those with reduced sperm motility. The adenine allele of the variant rs147729934 is potentially an informative tool for future population studies concerning ancient Baltic and Finno-Ugric history.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000481434DOI Listing
November 2017

Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus.

Sci Rep 2017 08 8;7(1):7512. Epub 2017 Aug 8.

UCL Institute of Ophthalmology, London, UK.

Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication including IRX1 (MCDR3) have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies on eighteen NCMD families, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream of IRX1 and upstream of ADAMTS16. One duplication of 43 kb was identified in nine families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. Three families carry the previously reported V2 variant (MCDR1), while five remain unsolved. The MCDR3 locus is thus refined to a shared region of 39 kb that contains DNAse hypersensitive sites active at a restricted time window during retinal development. Publicly available data confirmed expression of IRX1 and ADAMTS16 in human fetal retina, with IRX1 preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD and provide insights into the genetic pathways involved in human macular development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-06387-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548758PMC
August 2017

Genetic linkage studies of a North Carolina macular dystrophy family.

Medicina (Kaunas) 2016 19;52(3):180-6. Epub 2016 Apr 19.

Latvian Biomedical Research and Study Center, Riga, Latvia; Centre Hospitalier De l'Université Laval, Québec, Canada. Electronic address:

Background And Objective: North Carolina macular dystrophy (NCMD) is a very rare autosomal dominant hereditary disease. Up to date there are three types of NCMD described and consequently named macular dystrophy, retinal: MCDR1, MCDR2 and MCDR3. The aim of this study was to perform linkage and copy number variation analysis for the family affected by NCMD followed by the selected candidate gene sequencing.

Materials And Methods: This study concerned a 3-generation, non-consanguineous Latvian family with NCMD. Genome-wide scan, copy number variation and non-parametric linkage analysis was performed. Analysis resolved the locus of interest to the 5p15.33 region. Two of the genes, iroquois homeobox 2 (IRX2) and iroquois homeobox 4 (IRX4), were selected and sanger sequencing was performed.

Results: Linkage analysis indicated a region on chromosome 5 for the analyzed family, corresponding to a genetic locus previously described for MCDR3 (5p15-p13). Chromosomal aberrations were not identified in the affected family members. An upstream intron variant (NM_001278634: c.-139G > A (rs6876836)) in IRX4 gene segregated with NCMD phenotype in the analyzed family.

Conclusions: It is unlikely to be the causative mutation of NCMD due to its high minor allele frequency 0.3532. Therefore, the role of IRX2 and IRX4 genes in the pathogenesis of NCMD has not been proved. Considerable variability in visual acuity between individuals of the same age group in all the families examined was noted. No overlap between NCMD grade and family generation was seen in the family described in the present study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.medici.2016.04.001DOI Listing
October 2017

Analysis of possible genetic risk factors contributing to development of childhood acute lymphoblastic leukaemia in the Latvian population.

Arch Med Sci 2016 Jun 18;12(3):479-85. Epub 2016 May 18.

Latvian Biomedical Research and Study Centre, Riga, Latvia.

Introduction: Childhood acute lymphoblastic leukaemia (ALL) is a complex disease caused by a combination of genetic susceptibility and environmental exposure. Previous genome-wide association studies have reported several single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. Several variations in genes encoding enzymes involved in carcinogenesis are suggested as being associated with an increased risk of ALL development.

Material And Methods: We enrolled 77 paediatric ALL patients and 122 healthy controls, and in addition parental DNA was also available for 45 probands. SNPs rs10821936 (ARID5B), rs4132601 (IKZF1), rs2239633 (CEBPE), rs3731217 (CDKN2A) and rs1800566 (NQO1) and the presence of GSTT1 and GSTM1 null variants were detected. For statistical analysis the hybrid method of two designs 'Haplin' was used as well as linkage disequilibrium for family-based association studies.

Results: We identified the SNP rs10821936 in the ARID5B gene as being statistically significantly associated with childhood ALL, especially if the C allele is in a homozygous state, relative risk (RR) 4.65, 95% CI: 2.03-10.6, p = 0.0006. Statistically significant differences were not found in other SNPs. We found risk combinations including all five variations, the strongest association being found in a combination where all five genetic variants are in a homozygous state, CCTTTTTTCC, p = 0.032.

Conclusions: The identified SNP rs10821936 could serve as a potential risk marker for childhood ALL development. Further studies in an independent population are needed for verification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5114/aoms.2016.59920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889682PMC
June 2016

Robust genotyping tool for autosomal recessive type of limb-girdle muscular dystrophies.

BMC Musculoskelet Disord 2016 May 4;17:200. Epub 2016 May 4.

Biomedical Research and Study Centre, Ratsupites str. 1, k-1, LV-1067, Riga, Latvia.

Background: Limb-girdle muscular dystrophies are characterized by predominant involvement of the shoulder and pelvic girdle and trunk muscle groups. Currently, there are 31 genes implicated in the different forms of limb-girdle muscular dystrophies, which exhibit similar phenotypes and clinical overlap; therefore, advanced molecular techniques are required to achieve differential diagnosis.

Methods: We investigated 26 patients from Latvia and 34 patients from Lithuania with clinical symptoms of limb-girdle muscular dystrophies, along with 565 healthy unrelated controls from general and ethnic populations using our developed test kit based on the Illumina VeraCode GoldenGate genotyping platform, Ion AmpliSeq Inherited Disease Panel and direct sequencing of mutations in calpain 3 (CAPN3), anoctamin 5 (ANO5) and fukutin related protein (FKRP) genes.

Results: Analysis revealed a homozygous CAPN3 c.550delA mutation in eight patients and three heterozygous variants in controls: dysferlin (DYSF) c.5028delG, CAPN3 c.2288A > G, and FKRP c.135C > T. Additionally, three mutations within FKRP gene were found: homozygous c.826C > A, and two compound - c.826C > A/c.404_405insT and c.826C > A/c.204_206delCTC mutations, and one mutation within CLCN1 gene - c.2680C > T p.Arg894Ter. ANO5 c.191dupA was not present.

Conclusions: Genetic diagnosis was possible in 12 of 60 patients (20%). The allele frequency of CAPN3 gene mutation c.550delA in Latvia is 0.0016 and in Lithuania - 0.0029. The allele frequencies of CAPN3 gene mutation c.2288A > G and DYSF gene mutation c.4872delG are 0.003.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12891-016-1058-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855345PMC
May 2016

Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate.

Am J Hum Genet 2016 Apr 24;98(4):755-62. Epub 2016 Mar 24.

Medical Genetics and Mitochondrial Research Group, Latvian Biomedical Research and Study Centre, Riga 1067, Latvia.

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833214PMC
April 2016

Y-Chromosomal Lineages of Latvians in the Context of the Genetic Variation of the Eastern-Baltic Region.

Ann Hum Genet 2015 Nov 28;79(6):418-30. Epub 2015 Sep 28.

Latvian Biomedical Research and Study Centre, Riga, Latvia.

Variations of the nonrecombining Y-chromosomal region were investigated in 159 unrelated Baltic-speaking ethnic Latvians from four different geographic regions, using 28 biallelic markers and 12 short tandem repeats. Eleven different haplogroups (hgs) were detected in a regionally homogeneous Latvian population, among which N1c, R1a, and I1 cover more than 85% of its paternal lineages. When compared its closest geographic neighbors, the composition of the Latvian Y-chromosomal gene pool was found to be very similar to those of Lithuanians and Estonians. Despite the comparable frequency distribution of hg N1c in Latvians and Lithuanians with the Finno-Ugric-speaking populations from the Eastern coast of the Baltic Sea, the observed differences in allelic variances of N1c haplotypes between these two groups are in concordance with the previously stated hypothesis of different dispersal ways of this lineage in the region. More than a third of Latvian paternal lineages belong specifically to a recently defined R1a-M558 hg, indicating an influence from a common source within Eastern Slavic populations on the formation of the present-day Latvian Y-chromosome gene pool.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ahg.12130DOI Listing
November 2015

Presentation of Complex Homozygous Allele in ABCA4 Gene in a Patient with Retinitis Pigmentosa.

Case Rep Ophthalmol Med 2015 2;2015:452068. Epub 2015 Jul 2.

Biomedical Research and Study Centre, Riga LV-1067, Latvia.

Retinitis pigmentosa is a degenerative retinal disease characterized by progressive photoreceptor damage, which causes loss of peripheral and night vision and the development of tunnel vision and may result in loss of central vision. This study describes a patient with retinitis pigmentosa caused by a mutation in the ABCA4 gene with complex allele c.1622T>C, p.L541P; c.3113C>T, p.A1038V in homozygous state.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2015/452068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503555PMC
August 2015

Lack of association between polymorphisms in genes MTHFR and MDR1 with risk of childhood acute lymphoblastic leukemia.

Asian Pac J Cancer Prev 2014 ;15(22):9707-11

Riga Stradins University, Latvia E-mail :

Background: Acute lymphoblastic leukemia (ALL) is a complex disease caused by interactions between hazardous exogenous or/and endogenous agents and many mild effect inherited susceptibility mutations. Some of them are known, but their functional roles still requireinvestigation. Age is a recognized risk factor; children with disease onset after the age of ten have worse prognosis, presumably also triggered by inherited factors.

Materials And Methods: The MDR1 gene polymorphisms rs1045642, rs2032582 and MTHFR gene polymorphisms rs1801131 and rs1801133 were genotyped in 68 ALL patients in remission and 102 age and gender matched controls; parental DNA samples were also available for 42 probands.

Results: No case control association was found between analyzed polymorphisms and a risk of childhood ALL development. Linkage disequilibrium was not observed in a family-based association study either. Only marginal association was observed between genetic marker rs2032582A and later disease onset (p=0.04).

Conclusions: Our data suggest that late age of ALL onset could be triggered by mild effect common alleles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7314/apjcp.2014.15.22.9707DOI Listing
August 2015

Association of BMP4 polymorphisms with non-syndromic cleft lip with or without cleft palate and isolated cleft palate in Latvian and Lithuanian populations.

Stomatologija 2014 ;16(3):94-101

Scientific Laboratory of Molecular Genetics, Rīga Stradiņš University, Dzirciema street 16, LV-1007, Riga, Latvia.

Cleft lip with or without cleft palate (CLP and CL, respectively) and isolated cleft palate (CP) represent one of the most common human birth defects, with a prevalence of approximately 1 in 300-2500 depending on the population. Formation of non-syndromic CL/CLP and CP arises from the interaction of environmental and genetic factors. The objective of this study was to investigate the association between the BMP4 gene (encoding bone morphogenetic protein 4) and non-syndromic CL/CLP and CP in order to clarify the role of this gene in the aetiology of the malformation in Latvian and Lithuanian populations. We genotyped three markers of the BMP4 gene (rs17563, rs2071047 and rs1957860) in order to perform single marker and haplotype association analyses for Latvian and Lithuanian non-syndromic CL/CLP and CP patients and controls. Transmission disequilibrium test was also conducted for Latvian and Lithuanian proband-parent trios. The case-control analysis revealed that SNP rs2071047 allele A was associated with a decreased risk of CL/CLP in the Latvian population, which was confirmed by the haplotype analysis. A modest association was detected between SNP rs1957860 and CP in the Lithuanian population, where allele C was associated with a decreased risk of this cleft phenotype, corroborating haplotype analysis data. Our findings support a role of the BMP4 gene in the aetiology of non-syndromic CL/CLP and CP in the studied populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2016

Association between inherited monogenic liver disorders and chronic hepatitis C.

World J Hepatol 2014 Feb;6(2):92-7

Linda Piekuse, Madara Kreile, Agnese Zarina, Zane Steinberga, Scientific Laboratory of Molecular Genetics, Riga Stradins University, Riga LV-1007, Latvia.

Aim: To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C.

Methods: This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing.

Results: The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087).

Conclusion: Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4254/wjh.v6.i2.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935058PMC
February 2014

IRF6 AP-2a binding site promoter polymorphism is associated with oral clefts in Latvia.

Stomatologija 2014 ;16(4):132-6

Department of Pediatric Dentistry, Institute of Stomatology, Dzirciema 20, Riga LV1007, Latvia.

Objective: To evaluate the association between AXIN2, CDH1 and IRF6 with oral clefts in a cohort from Latvia.

Material And Methods: 283 unrelated individuals, 93 born with isolated oral clefts and 190 individuals born without any structural abnormalities were evaluated. Cleft type and dental anomalies outside the cleft area were determined by clinical examination. Four SNPs were selected for this study: rs2240308 and rs11867417 in AXIN2; rs9929218 in CDH1; and rs642961 in IRF6. Genotypes were determined by polymerase chain reaction using the Taqman assay method from a genomic DNA sample extracted from whole blood. Allele and genotype frequencies were compared between individuals born with or without oral clefts using the PLINK program.

Results: Tooth agenesis was the most frequent dental anomaly found among individuals born with oral clefts (N=10; frequency 10.8%). The allele A in the IRF6 marker rs642961 was associated with all combined types of oral clefts (OR=1.74; CI 95% 1.07-2.82) and with cases with cleft lip with or without cleft palate (OR=1.88, CI 95% 1.15-3.01; p=0.007).

Conclusions: The IRF6 AP-2a binding site promoter polymorphism is associated with isolated oral clefts in Latvia.
View Article and Find Full Text PDF

Download full-text PDF

Source
May 2016

Dupuytren's Contracture Cosegregation with Limb-Girdle Muscle Dystrophy.

Case Rep Neurol Med 2013 19;2013:254950. Epub 2013 Aug 19.

Latvian Biomedical Research and Study Centre, Ratsupites Street 1, Riga 1067, Latvia.

Limb-girdle muscular dystrophies (LGMDs) is a heterogeneous group of muscular dystrophies that mostly affect the pelvic and shoulder girdle muscle groups. We report here a case of neuromuscular disease associated with Dupuytren's contracture, which has never been described before as cosegregating with an autosomal dominant type of inheritance. Dupuytren's contracture is a common disease, especially in Northern Europe. Comorbid conditions associated with Dupuytren's contracture are repetitive trauma to the hands, diabetes, and seizures, but it has never before been associated with neuromuscular disease. We hypothesize that patients may harbor mutations in genes with functions related to neuromuscular disease and Dupuytren's contracture development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2013/254950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760302PMC
September 2013

Genetic variation in the promoter region of beta-defensin 1 (DEFB 1) is associated with high caries experience in children born with cleft lip and palate.

Acta Odontol Scand 2014 Apr 22;72(3):235-40. Epub 2013 Aug 22.

Department of Pediatric Dentistry, Riga Stradins University Institute of Stomatology , Riga, Latvia.

Objective: Caries is a common disease in humans and has a multifactorial etiology. It has been suggested that children born with cleft lip and/or palate (CL/P) have a higher susceptibility to caries, but data from several independent cohorts does not support this assumption. Previous work from our group suggested DEFB 1 is associated with higher caries experience. Since it is suspected that children born with CL/P have the same risk factors predisposing them to caries as other children of the same ages, the aim was to test if DEFB 1 was associated with caries experience in children born with CL/P.

Materials And Methods: Sixty-nine children born with CL/P (aged 2-12 years) were included. Twenty-seven males and seven females had cleft lip and palate (CLP), six males and seven females had cleft lip (CL) and 13 males and nine females had cleft palate (CP). Caries was evaluated with the DMFT/dmft index by a calibrated evaluator. Two single nucleotide polymorphisms in DEFB 1 were selected (rs11362 and rs1800972) based on being associated with higher caries experience in previous work. Genotyping were carried out by real-time PCR using the Taqman assay method. The statistical analysis was performed between 'low-to-moderate caries experience group' and the 'high caries experience group'. Odds ratio calculations between caries experience and variant alleles and chi-square of Fisher exact tests at a level of significance of 0.05 were used.

Results: There was no significant difference for caries experience between cleft types (p = 0.551). An association was found for the marker rs11362 and genotype distribution (p = 0.047). When analyzed in a recessive model, the genotype GG in this polymorphism increased the risk for caries susceptibility by more than 3-times (p = 0.031; OR = 3.16; 95% CI = 0.97-10.62).

Conclusion: The genetic variant rs11362 in DEFB 1 influences caries susceptibility in CL/P children. The results support the hypothesis that expression of DEFB 1 in saliva may serve as a biomarker for future caries risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/00016357.2013.822549DOI Listing
April 2014

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa.

Eur J Hum Genet 2014 Jul 21;22(7):888-95. Epub 2013 Aug 21.

1] Department of Pediatrics, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands [2] Hayward Genetics Center, Tulane University Medical Center, New Orleans, LA, USA.

Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2013.154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060105PMC
July 2014

BCL3 gene role in facial morphology.

Birth Defects Res A Clin Mol Teratol 2012 Nov 1;94(11):918-24. Epub 2012 Nov 1.

Latvian Biomedical Study and Research Centre, Riga, Latvia.

Background: Cleft lip (CL) with or without palate (CLP) and isolated cleft palate (CP) are etiologically complex diseases with interactions among various environmental and genetic factors. The aim of the current study was to identify association with genetic markers and phenotypic craniofacial data in patients with CL/CLP/CP parents.

Methods: Posteroanterior and lateral digital radiographs of the cranium were obtained from 74 parents of patients with CL/CLP/CP. One hundred seventy-three patients with CL/CLP/CP and 190 controls were enrolled in the study for the association test. Five genetic markers of the IRF6 gene and 14 markers of the 19q13 locus were genotyped. Linear regression analysis was performed for the relationship of cephalometric measurements with genotype data adjusted for age, gender, and cleft type. Chi-square and transmission disequilibrium tests were performed to evaluate differences in alleles of the BCL3 gene. Positive findings were replicated in an independent sample (n = 95) of patients with CL/CLP/CP parents.

Results: Genetic markers of the BCL3 gene at 19q13, rs7257231, and rs1979377 in the familial association test and rs10401176 in the case-control association test, were associated with craniofacial phenotype. Carriers of BCL3 allele rs7257231T had longer posterior cranial bases than noncarriers (p(adjusted) = 0.0028), and in the familial-based association test showed the statistically strongest relationship (p(adjusted) = 0.05) to phenotype. Relation of rs7257231 to facial formation was confirmed in the replication group (p = 0.0024).

Conclusions: The results indicate that BCL3, which has functions related to cell adhesion and whose downregulation can cause disruption of ectodermal development, is likely to be important in facial formation. Birth Defects Research (Part A), 2012.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdra.23085DOI Listing
November 2012

Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate.

PLoS One 2012 20;7(9):e45441. Epub 2012 Sep 20.

Department of Oral Biology, University of Pittsburgh, School of Dental Medicine, Pittsburgh, PA, USA.

Previous evidence from tooth agenesis studies suggested IRF6 and TGFA interact. Since tooth agenesis is commonly found in individuals with cleft lip/palate (CL/P), we used four large cohorts to evaluate if IRF6 and TGFA interaction contributes to CL/P. Markers within and flanking IRF6 and TGFA genes were tested using Taqman or SYBR green chemistries for case-control analyses in 1,000 Brazilian individuals. We looked for evidence of gene-gene interaction between IRF6 and TGFA by testing if markers associated with CL/P were overtransmitted together in the case-control Brazilian dataset and in the additional family datasets. Genotypes for an additional 142 case-parent trios from South America drawn from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), 154 cases from Latvia, and 8,717 individuals from several cohorts were available for replication of tests for interaction. Tgfa and Irf6 expression at critical stages during palatogenesis was analyzed in wild type and Irf6 knockout mice. Markers in and near IRF6 and TGFA were associated with CL/P in the Brazilian cohort (p<10(-6)). IRF6 was also associated with cleft palate (CP) with impaction of permanent teeth (p<10(-6)). Statistical evidence of interaction between IRF6 and TGFA was found in all data sets (p = 0.013 for Brazilians; p = 0.046 for ECLAMC; p = 10(-6) for Latvians, and p = 0.003 for the 8,717 individuals). Tgfa was not expressed in the palatal tissues of Irf6 knockout mice. IRF6 and TGFA contribute to subsets of CL/P with specific dental anomalies. Moreover, this potential IRF6-TGFA interaction may account for as much as 1% to 10% of CL/P cases. The Irf6-knockout model further supports the evidence of IRF6-TGFA interaction found in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045441PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3447924PMC
February 2013
-->