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RECURRENT CNVS AND SNVS AT THE NPHP1 LOCUS CONTRIBUTE PATHOGENIC ALLELES TO BARDET-BIEDL SYNDROME
DNA Copy Number Variations
Kidney/abnormalities
Membrane Proteins/genetics
Mice
Sequence Deletion
Autor(es)
Afiliação
Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA/Karolinska Institute. Department of Molecular Medicine & Surgery. Stockholm, Sweden
Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG, Brazil
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA
Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA
Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA
Loma Linda University School of Medicine. Department of Pediatrics. Division of Medical Genetics. Loma Linda, CA, USA
Loma Linda University School of Medicine. Pathology and Human Anatomy. Loma Linda, CA, USA
Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA
Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA
Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA
Hadassah-Hebrew University Medical Center. Center for Retinal and Macular Degenerations. Department of Ophthalmology. Jerusalem, Israel
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Baylor College of Medicine and Texas Children’s Hospital. Departments of Molecular and Human Genetics and Pediatrics. Houston, TX, USA
Loma Linda University School of Medicine. Department of Pediatrics. Division of Medical Genetics. Loma Linda, CA, USA
Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA
Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG, Brazil
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA
Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA
Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA
Loma Linda University School of Medicine. Department of Pediatrics. Division of Medical Genetics. Loma Linda, CA, USA
Loma Linda University School of Medicine. Pathology and Human Anatomy. Loma Linda, CA, USA
Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA
Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA
Baylor College of Medicine. Human Genome Sequencing Center. Houston, TX, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA
Hadassah-Hebrew University Medical Center. Center for Retinal and Macular Degenerations. Department of Ophthalmology. Jerusalem, Israel
Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Baylor College of Medicine and Texas Children’s Hospital. Departments of Molecular and Human Genetics and Pediatrics. Houston, TX, USA
Loma Linda University School of Medicine. Department of Pediatrics. Division of Medical Genetics. Loma Linda, CA, USA
Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA
Resumo em Inglês
Homozygosity for a recurrent 290 kb deletion of NPHP1 is the most frequent cause of isolated nephronophthisis (NPHP) in humans. A deletion of the same genomic interval has also been detected in individuals with Joubert syndrome (JBTS), and in the mouse, Nphp1 interacts genetically with Ahi1, a known JBTS locus. Given these observations, we investigated the contribution of NPHP1 in Bardet-Biedl syndrome (BBS), a ciliopathy of intermediate severity. By using a combination of array-comparative genomic hybridization, TaqMan copy number assays, and sequencing, we studied 200 families affected by BBS. We report a homozygous NPHP1 deletion CNV in a family with classical BBS that is transmitted with autosomal-recessive inheritance. Further, we identified heterozygous NPHP1 deletions in two more unrelated persons with BBS who bear primary mutations at another BBS locus. In parallel, we identified five families harboring an SNV in NPHP1 resulting in a conserved missense change, c.14G>T (p.Arg5Leu), that is enriched in our Hispanic pedigrees; in each case, affected individuals carried additional bona fide pathogenic alleles in another BBS gene. In vivo functional modeling in zebrafish embryos demonstrated that c.14G>T is a loss-of-function variant, and suppression of nphp1 in concert with each of the primary BBS loci found in our NPHP1-positive pedigrees exacerbated the severity of the phenotype. These results suggest that NPHP1 mutations are probably rare primary causes of BBS that contribute to the mutational burden of the disorder.
Palavras-chave em inglês
Bardet-Biedl Syndrome/geneticsDNA Copy Number Variations
Kidney/abnormalities
Membrane Proteins/genetics
Mice
Sequence Deletion
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