Publications by authors named "Mara Marongiu"

16 Publications

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Complex genetic signatures in immune cells underlie autoimmunity and inform therapy.

Nat Genet 2020 10 14;52(10):1036-1045. Epub 2020 Sep 14.

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Cagliari, Italy.

We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.
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http://dx.doi.org/10.1038/s41588-020-0684-4DOI Listing
October 2020

Overexpression of the Cytokine BAFF and Autoimmunity Risk.

N Engl J Med 2017 04;376(17):1615-1626

From Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (M.S., V.O., M.L.I., M. Pitzalis, M. Pala, C.S., V.F., M.F., M. Deiana, I.A., E.P., A. Mulas, M.G.P., M. Lobina, S.L., Mara Marongiu, V.S., Michele Marongiu, G.S., F.B., A. Maschio, F.D., M. Dei, F.V., S.O., A.A., M.B.W., A. Meloni, S. Sanna, E.F., M.Z., F.C.), Center for Advanced Studies, Research, and Development in Sardinia, Parco Scientifico e Tecnologico della Sardegna (I.Z., M.F., R.C., G. Cuccuru), Struttura Complessa Disciplina di Ematologia e Centro Trapianto Cellule Staminali Emopoietiche Wilma Deplano, Ospedale Oncologico di Riferimento Regionale Armando Businco (M. Pani), Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università di Cagliari (E.C., J.F., G. Coghe, L.L., G. Fenu), Azienda Ospedaliera Brotzu, S.C. Neurologia (P.F., M. Melis), Division of Rheumatology, University and University Hospital of Cagliari (M. Piga, A. Mathieu), Department of Medical Sciences M. Aresu, University of Cagliari (D.F., S.D.G., M.G.M.), Azienda Ospedaliera Brotzu, U.S. Gastroenterologia Pediatrica Ospedale Pediatrico Microcitemico A. Cao (M.C.), and Nephrology, Dialysis, and Transplantation Unit, Giuseppe Brotzu Hospital (A.P.), Cagliari, Dipartimento di Scienze Biomediche, Università degli Studi di Sassari (M.F., F.P., F.C.), Unit of Neurology, Department of Clinical and Experimental Medicine, University of Sassari (G. Farina, G.R.), and Servizio Trasfusionale (M.A.S.) and Clinica Medica (A.D.), Azienda Ospedaliero Universitaria di Sassari, Sassari, Neurology B, Department of Neurological, Biomedical, and Movement Sciences, University of Verona, Verona (G. Farina), Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont, Novara (N.B., S.D.), SC Neurologia, Dipartimento di Scienze Mediche, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo (M. Leone), Don C. Gnocchi Foundation IRCCS (F.R.G.), and Referral Center for Systemic Autoimmune Diseases Fondazione IRCCS Cá Granda Ospedale Maggiore Policlinico and University of Milan (M. Marchini), Milan, and Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche e Ospedali Riuniti, Ancona (M.G.D.) - all in Italy; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore (M.L.I., M.G., D.S.); the Department of Clinical Neurosciences (M.B., S. Sawcer) and JDRF-Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research (J.A.T.), University of Cambridge, Cambridge, United Kingdom; Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital Solna (I.K., I.L.B., T.O., J.H.), Institute of Environmental Medicine (L.A.) and Institute of Environmental Medicine, Unit of Immunology and Chronic Disease (M.E.A.R.), Karolinska Institute, and Center for Occupational and Environmental Medicine, Stockholm County Council (L.A.), Stockholm; Department of Functional Biology, University of Oviedo, Oviedo (A.S.), Rheumatology Department, Hospital Universitario 12 de Octubre, Madrid (P.E.C.), Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Seville (M.J.C.-P.), Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela (A.G.), and Centro de Genómica e Investigación Oncológica, Pfizer-Universidad de Granada-Junta de Andalucía, Granada (M.E.A.R.) - all in Spain; Department of Human Genetics, University of Chicago, Chicago (J.H.M., J.N.); Centro Hospitalar do Porto-Hospital Santo Antonio and Unit for Multidisciplinary Research in Biomedicine-Unidade Multidisciplinar de Investigação Biomédica, Porto, Portugal (B.M.S.); Departments of Pathology and Genetics, Stanford University, Stanford, CA (S.B.M.); and Center for Statistical Genetics, University of Michigan, Ann Arbor (G.R.A.).

Background: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways.

Methods: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated.

Results: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria.

Conclusions: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).
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http://dx.doi.org/10.1056/NEJMoa1610528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605835PMC
April 2017

Population- and individual-specific regulatory variation in Sardinia.

Nat Genet 2017 May 10;49(5):700-707. Epub 2017 Apr 10.

Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.

Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.
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http://dx.doi.org/10.1038/ng.3840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411016PMC
May 2017

Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa.

Am J Hum Genet 2016 Jul;99(1):236-45

Department of General Pediatrics, Münster University Children's Hospital, 48149 Münster, Germany.

Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) is a very rare autosomal-recessive disorder characterized by a complex phenotype with high neonatal lethality, associated with the following main clinical features: hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold since early childhood. CS/CISS1 can be caused by mutations in cytokine receptor-like factor 1 (CRLF1). However, the physiopathological role of CRLF1 is still poorly understood. A subset of CS/CISS1 cases remain yet genetically unexplained after CRLF1 sequencing. In five of them, exome sequencing and targeted Sanger sequencing identified four homozygous disease-causing mutations in kelch-like family member 7 (KLHL7), affecting the Kelch domains of the protein. KLHL7 encodes a BTB-Kelch-related protein involved in the ubiquitination of target proteins for proteasome-mediated degradation. Mono-allelic substitutions in other domains of KLHL7 have been reported in three families affected by a late-onset form of autosomal-dominant retinitis pigmentosa. Retinitis pigmentosa was also present in two surviving children reported here carrying bi-allelic KLHL7 mutations. KLHL7 mutations are thus associated with a more severe phenotype in recessive than in dominant cases. Although these data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype, they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7.
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http://dx.doi.org/10.1016/j.ajhg.2016.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005468PMC
July 2016

Novel action of FOXL2 as mediator of Col1a2 gene autoregulation.

Dev Biol 2016 08 19;416(1):200-211. Epub 2016 May 19.

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy. Electronic address:

FOXL2 belongs to the evolutionarily conserved forkhead box (FOX) superfamily and is a master transcription factor in a spectrum of developmental pathways, including ovarian and eyelid development and bone, cartilage and uterine maturation. To analyse its action, we searched for proteins that interact with FOXL2. We found that FOXL2 interacts with specific C-terminal propeptides of several fibrillary collagens. Because these propeptides can participate in feedback regulation of collagen biosynthesis, we inferred that FOXL2 could thereby affect the transcription of the cognate collagen genes. Focusing on COL1A2, we found that FOXL2 indeed affects collagen synthesis, by binding to a DNA response element located about 65Kb upstream of this gene. According to our hypothesis we found that in Foxl2(-/-) mouse ovaries, Col1a2 was elevated from birth to adulthood. The extracellular matrix (ECM) compartmentalizes the ovary during folliculogenesis, (with type I, type III and type IV collagens as primary components), and ECM composition changes during the reproductive lifespan. In Foxl2(-/-) mouse ovaries, in addition to up-regulation of Col1a2, Col3a1, Col4a1 and fibronectin were also upregulated, while laminin expression was reduced. Thus, by regulating levels of extracellular matrix components, FOXL2 may contribute to both ovarian histogenesis and the fibrosis attendant on depletion of the follicle reserve during reproductive aging and menopause.
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http://dx.doi.org/10.1016/j.ydbio.2016.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526220PMC
August 2016

FOXL2 modulates cartilage, skeletal development and IGF1-dependent growth in mice.

BMC Dev Biol 2015 Jul 2;15:27. Epub 2015 Jul 2.

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, SS 554 km 4500, Monserrato, 09042, Italy.

Background: Haploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and premature ovarian failure. Mice lacking Foxl2 recapitulate human eyelid/forehead defects and undergo female gonadal dysgenesis. We report here that mice lacking Foxl2 also show defects in postnatal growth and embryonic bone and cartilage formation.

Methods: Foxl2 (-/-) male mice at different stages of development have been characterized and compared to wild type. Body length and weight were measured and growth curves were created. Skeletons were stained with alcian blue and/or alizarin red. Bone and cartilage formation was analyzed by Von Kossa staining and immunofluorescence using anti-FOXL2 and anti-SOX9 antibodies followed by confocal microscopy. Genes differentially expressed in skull vaults were evaluated by microarray analysis. Analysis of the GH/IGF1 pathway was done evaluating the expression of several hypothalamic-pituitary-bone axis markers by RT-qPCR.

Results: Compared to wild-type, Foxl2 null mice are smaller and show skeletal abnormalities and defects in cartilage and bone mineralization, with down-regulation of the GH/IGF1 axis. Consistent with these effects, we find FOXL2 expressed in embryos at 9.5 dpc in neural tube epithelium, in head mesenchyme near the neural tube, and within the first branchial arch; then, starting at 12.5 dpc, expressed in cartilaginous tissue; and at PO and P7, in hypothalamus.

Conclusions: Our results support FOXL2 as a master transcription factor in a spectrum of developmental processes, including growth, cartilage and bone formation. Its action overlaps that of SOX9, though they are antagonistic in female vs male gonadal sex determination but conjoint in cartilage and skeletal development.
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http://dx.doi.org/10.1186/s12861-015-0072-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489133PMC
July 2015

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.

Nat Genet 2012 Jan 22;44(3):260-8. Epub 2012 Jan 22.

Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
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http://dx.doi.org/10.1038/ng.1051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288642PMC
January 2012

SUMOylation of the Forkhead transcription factor FOXL2 promotes its stabilization/activation through transient recruitment to PML bodies.

PLoS One 2011 12;6(10):e25463. Epub 2011 Oct 12.

Programme de Pathologie Moléculaire et Cellulaire, Institut Jacques Monod, UMR 7592 CNRS-Université Paris Diderot, Paris, France.

Background: FOXL2 is a transcription factor essential for ovarian development and maintenance. It is mutated in the genetic condition called Blepharophimosis Ptosis Epicantus inversus Syndrome (BPES) and in cases of isolated premature ovarian failure. We and others have previously shown that FOXL2 undergoes several post-translational modifications.

Methods And Principal Findings: Here, using cells in culture, we show that interference with FOXL2 SUMOylation leads to a robust inhibition of its transactivation ability, which correlates with a decreased stability. Interestingly, FOXL2 SUMOylation promotes its transient recruitment to subnuclear structures that we demonstrate to be PML (Promyelocytic Leukemia) Nuclear Bodies. Since PML bodies are known to be sites where post-translational modifications of nuclear factors take place, we used tandem mass spectrometry to identify new post-translational modifications of FOXL2. Specifically, we detected four phosphorylated, one sulfated and three acetylated sites.

Conclusions: By analogy with other transcription factors, we propose that PML Nuclear Bodies might transiently recruit FOXL2 to the vicinity of locally concentrated enzymes that could be involved in the post-translational maturation of FOXL2. FOXL2 acetylation, sulfation, phosphorylation as well as other modifications yet to be discovered might alter the transactivation capacity of FOXL2 and/or its stability, thus modulating its global intracellular activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025463PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192040PMC
February 2012

Differential secretion of the mutated protein is a major component affecting phenotypic severity in CRLF1-associated disorders.

Eur J Hum Genet 2011 May 16;19(5):525-33. Epub 2011 Feb 16.

Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.

Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) are disorders caused by mutations in CRLF1. The two syndromes share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia, associated with death in most cases in the first years of life. To evaluate a potential genotype/phenotype correlation and whether CS and CISS1 represent two allelic diseases or manifestations at different ages of the same disorder, we carried out a detailed clinical analysis of 19 patients carrying mutations in CRLF1. We studied the functional significance of the mutations found in CRLF1, providing evidence that phenotypic severity of the two disorders mainly depends on altered kinetics of secretion of the mutated CRLF1 protein. On the basis of these findings, we believe that the two syndromes, CS and CISS1, represent manifestations of the same disorder, with different degrees of severity. We suggest renaming the two genetic entities CS and CISS1 with the broader term of Sohar-Crisponi syndrome.
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http://dx.doi.org/10.1038/ejhg.2010.253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083629PMC
May 2011

Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.

Nat Genet 2010 Dec;42(12):1077-85

Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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http://dx.doi.org/10.1038/ng.714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140055PMC
December 2010

The forkhead transcription factor Foxl2 is sumoylated in both human and mouse: sumoylation affects its stability, localization, and activity.

PLoS One 2010 Mar 2;5(3):e9477. Epub 2010 Mar 2.

Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari, Italy.

The FOXL2 forkhead transcription factor is expressed in ovarian granulosa cells, and mutated FOXL2 causes the blepharophimosis, ptosis and epicanthus inversus syndrome (BPES) and predisposes to premature ovarian failure. Inactivation of Foxl2 in mice demonstrated its indispensability for female gonadal sex determination and ovary development and revealed its antagonism of Sox9, the effector of male testis development. To help to define the regulatory activities of FOXL2, we looked for interacting proteins. Based on yeast two-hybrid screening, we found that FOXL2 interacts with PIAS1 and UBC9, both parts of the sumoylation machinery. We showed that human FOXL2 is sumoylated in transfected cell lines, and that endogenous mouse Foxl2 is comparably sumoylated. This modification changes its cellular localization, stability and transcriptional activity. It is intriguing that similar sumoylation and regulatory consequences have also been reported for SOX9, the male counterpart of FOXL2 in somatic gonadal tissues.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830456PMC
March 2010

Withania somnifera prevents morphine withdrawal-induced decrease in spine density in nucleus accumbens shell of rats: a confocal laser scanning microscopy study.

Neurotox Res 2009 Nov 24;16(4):343-55. Epub 2009 Jun 24.

Department of Toxicology, University of Cagliari, 09124 Cagliari, Italy.

Opiate withdrawal is associated with morphological changes of dopamine neurons in the ventral tegmental area and with reduction of spine density of second-order dendrites of medium size spiny neurons in the nucleus accumbens shell but not core. Withania somnifera has long been used in the Middle East, Africa, and India as a remedy for different conditions and diseases and a growing body of evidence points to its beneficial effects on a number of experimental models of neurological disorders. Recently, many studies focused on the potential neuritic regeneration and synaptic reconstruction properties of its methanolic extract and its constituents (withanolides). This study investigates whether morphine withdrawal-induced spine reduction in the nucleus accumbens is affected by the administration of a Withania somnifera extract. To this end, rats were chronically treated with Withania somnifera extract along with morphine or saline and, upon spontaneous (1 and 3 days) or pharmacologically precipitated withdrawal, their brains were fixed in Golgi-Cox stain for confocal microscopic examination. In a separate group of animals, Withania somnifera extract was administered during three days of spontaneous withdrawal. Withania somnifera extract treatment reduced the severity of the withdrawal syndrome when given during chronic morphine but not during withdrawal. In addition, treatment with Withania somnifera extract during chronic morphine, but not during withdrawal, fully prevented the reduction of spine density in the nucleus accumbens shell in spontaneous and pharmacologically precipitated morphine withdrawal. These results indicate that pretreatment with Withania somnifera extract protects from the structural changes induced by morphine withdrawal potentially providing beneficial effects on the consequences related to this condition.
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http://dx.doi.org/10.1007/s12640-009-9069-2DOI Listing
November 2009

Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia.

Hum Mol Genet 2009 Jul 6;18(14):2711-8. Epub 2009 May 6.

Istituto di Neurogenetica e Neurofarmacologia del Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.

Bilirubin, resulting largely from the turnover of hemoglobin, is found in the plasma in two main forms: unconjugated or conjugated with glucuronic acid. Unconjugated bilirubin is transported into hepatocytes. There, it is glucuronidated by UGT1A1 and secreted into the bile canaliculi. We report a genome wide association scan in 4300 Sardinian individuals for total serum bilirubin levels. In addition to the two known loci previously involved in the regulation of bilirubin levels, UGT1A1 (P = 6.2 x 10(-62)) and G6PD (P = 2.5 x 10(-8)), we observed a strong association on chromosome 12 within the SLCO1B3 gene (P = 3.9 x 10(-9)). Our findings were replicated in an independent sample of 1860 Sardinians and in 832 subjects from the Old Order Amish (combined P < 5 x 10(-14)). We also show that SLC01B3 variants contribute to idiopathic mild unconjugated hyperbilirubinemia. Thus, SLC01B3 appears to be involved in the regulation of serum bilirubin levels in healthy individuals and in some bilirubin-related disorders that are only partially explained by other known gene variants.
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http://dx.doi.org/10.1093/hmg/ddp203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701337PMC
July 2009

Crisponi syndrome is caused by mutations in the CRLF1 gene and is allelic to cold-induced sweating syndrome type 1.

Am J Hum Genet 2007 May 30;80(5):971-81. Epub 2007 Mar 30.

Istituto di Neurogenetica e Neurofarmacologia-Consiglio Nazionale delle Ricerche, Cittadella Universitaria di Monserrato, Monserrato, Italy.

Crisponi syndrome is a severe autosomal recessive condition that is phenotypically characterized by abnormal, paroxysmal muscular contractions resembling neonatal tetanus, large face, broad nose, anteverted nares, camptodactyly, hyperthermia, and sudden death in most cases. We performed homozygosity mapping in five Sardinian and three Turkish families with Crisponi syndrome, using high-density single-nucleotide polymorphism arrays, and identified a critical region on chromosome 19p12-13.1. The most prominent candidate gene was CRLF1, recently found to be involved in the pathogenesis of cold-induced sweating syndrome type 1 (CISS1). CISS1 belongs to a group of conditions with overlapping phenotypes, also including cold-induced sweating syndrome type 2 and Stuve-Wiedemann syndrome. All these syndromes are caused by mutations of genes of the ciliary neurotrophic factor (CNTF)-receptor pathway. Here, we describe the identification of four different CRLF1 mutations in eight different Crisponi-affected families, including a missense mutation, a single-nucleotide insertion, and a nonsense and an insertion/deletion (indel) mutation, all segregating with the disease trait in the families. Comparison of the mutation spectra of Crisponi syndrome and CISS1 suggests that neither the type nor the location of the CRLF1 mutations points to a phenotype/genotype correlation that would account for the most severe phenotype in Crisponi syndrome. Other, still-unknown molecular factors may be responsible for the variable phenotypic expression of the CRLF1 mutations. We suggest that the syndromes can comprise a family of "CNTF-receptor-related disorders," of which Crisponi syndrome would be the newest member and allelic to CISS1.
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http://dx.doi.org/10.1086/516843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852730PMC
May 2007