Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome.

TitleRecurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome.
Publication TypeJournal Article
Year of Publication2014
AuthorsLindstrand, 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
JournalAm J Hum Genet
Date Published2014 May 1
KeywordsAdaptor Proteins, Signal Transducing, Alleles, Animals, Bardet-Biedl Syndrome, DNA Copy Number Variations, Gastrulation, Genetic Loci, Heterozygote, Homozygote, Humans, Kidney, Membrane Proteins, Mice, Pedigree, Sequence Deletion, Zebrafish

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID24746959
PubMed Central IDPMC4067552
Grant ListR01 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
HD042601 / HD / NICHD NIH HHS / United States
P50 DK096415 / DK / NIDDK NIH HHS / United States
F32 DK094578 / DK / NIDDK NIH HHS / United States
EY021872 / EY / NEI NIH HHS / United States
R01 DK075972 / DK / NIDDK NIH HHS / United States
F32DK094578 / DK / NIDDK 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

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