Title | Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Lindstrand, A, Davis, EE, Carvalho, CMB, Pehlivan, D, Willer, JR, Tsai, I-C, Ramanathan, S, Zuppan, C, Sabo, A, Muzny, DM, Gibbs, RA, Liu, P, Lewis, RA, Banin, E, Lupski, JR, Clark, R, Katsanis, N |
Journal | Am J Hum Genet |
Volume | 94 |
Issue | 5 |
Pagination | 745-54 |
Date Published | 2014 May 01 |
ISSN | 1537-6605 |
Keywords | Adaptor Proteins, Signal Transducing, Alleles, Animals, Bardet-Biedl Syndrome, Cytoskeletal Proteins, DNA Copy Number Variations, Gastrulation, Genetic Loci, Heterozygote, Homozygote, Humans, Kidney, Membrane Proteins, Mice, Pedigree, Sequence Deletion, Zebrafish |
Abstract | 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. |
DOI | 10.1016/j.ajhg.2014.03.017 |
Alternate Journal | Am J Hum Genet |
PubMed ID | 24746959 |
PubMed Central ID | PMC4067552 |
Grant List | R01 EY021872 / EY / NEI NIH HHS / United States DK072301 / DK / NIDDK NIH HHS / United States DK075972-09 / DK / NIDDK NIH HHS / United States R01 DK072301 / DK / NIDDK NIH HHS / United States U54 HD083092 / HD / NICHD NIH HHS / United States F32 DK094578 / DK / NIDDK NIH HHS / United States EY021872 / EY / NEI NIH HHS / United States R01 NS058529 / NS / NINDS NIH HHS / United States R01 HD042601 / HD / NICHD NIH HHS / United States NS058529 / NS / NINDS NIH HHS / United States HD042601 / HD / NICHD NIH HHS / United States P50 DK096415 / DK / NIDDK NIH HHS / United States R01 DK075972 / DK / NIDDK NIH HHS / United States F32DK094578 / DK / NIDDK NIH HHS / United States |
Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome.
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