PUBLICATION

Recurrent CNVs and SNVs at the NPHP1 Locus Contribute Pathogenic Alleles to Bardet-Biedl Syndrome

Authors
Lindstrand, A., Davis, E.E., Carvalho, C.M., Pehlivan, D., Willer, J.R., Tsai, I.C., Ramanathan, S., Zuppan, C., Sabo, A., Muzny, D., Gibbs, R., Liu, P., Lewis, R.A., Banin, E., Lupski, J.R., Clark, R., Katsanis, N.
ID
ZDB-PUB-140513-124
Date
2014
Source
American journal of human genetics   94: 745-54 (Journal)
Registered Authors
Davis, Erica, Katsanis, Nicholas, Willer, Jason
Keywords
none
MeSH Terms
  • Adaptor Proteins, Signal Transducing/genetics*
  • Alleles
  • Animals
  • Bardet-Biedl Syndrome/genetics*
  • DNA Copy Number Variations*
  • Gastrulation/genetics
  • Genetic Loci
  • Heterozygote
  • Homozygote
  • Humans
  • Kidney/abnormalities
  • Membrane Proteins/genetics*
  • Mice
  • Pedigree
  • Sequence Deletion
  • Zebrafish/abnormalities
  • Zebrafish/genetics
PubMed
24746959 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping