Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome

Abstract

Meckel-Gruber syndrome (MKS) is a genetically heterogeneous, neonatally lethal malformation and the most common form of syndromic neural tube defect (NTD). To date, several MKS-associated genes have been identified whose protein products affect ciliary function. Here we show that mutations in MKS1, MKS3 and CEP290 (also known as NPHP6) either can cause Bardet-Biedl syndrome (BBS) or may have a potential epistatic effect on mutations in known BBS-associated loci. Five of six families with both MKS1 and BBS mutations manifested seizures, a feature that is not a typical component of either syndrome. Functional studies in zebrafish showed that mks1 is necessary for gastrulation movements and that it interacts genetically with known bbs genes. Similarly, we found two families with missense or splice mutations in MKS3, in one of which the affected individual also bears a homozygous nonsense mutation in CEP290 that is likely to truncate the C terminus of the protein. These data extend the genetic stratification of ciliopathies and suggest that BBS and MKS, although distinct clinically, are allelic forms of the same molecular spectrum.

Bardet–Biedl syndrome

“…39 It appears that the ciliopathy phenotype reflects both the specific mutated loci and the total mutational load. 39,40 Genotype-phenotype correlation Genotype-phenotype correlations are poor, although one study suggests a milder phenotype associated with the common M390R mutation found in BBS1. 15 Other studies have suggested that specific ocular phenotypes 41,42 and more severe digital abnormalities 42 may be linked to BBS2, BBS3 and BBS4 mutations.…”

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

“…15 In fact, mutations in MKS genes have been reported to cause other ciliopathies, for example, MKS1 and BardetBiedl syndrome, 16 TMEM216 and Joubert syndrome, 17 TMEM67 and Joubert syndrome and nephrophthisis, 18,19 CEP290 in non-syndromic retinal dystrophy, Senior-Loken syndrome, nephronophthisis, Joubert syndrome, and Bardet-Biedl syndrome, 20 RPGRIP1L and Joubert syndrome, 21 and CC2D2A and Joubert syndrome. 22 The factors that determine the ultimate clinical phenotype are not completely understood but there is growing evidence that ciliopathies represent a spectrum of clinical severity that correlates to some extent with the severity of the ciliary defect.…”

Arrayed primer extension technology simplifies mutation detection in Bardet–Biedl and Alström syndrome

“…[3][4][5] In addition, mutations in BBS patients have also been identified in MKS1 and CEP290, genes known to cause other ciliopathic phenotypes such as Meckel syndrome and nephronophthisis. 6 Owing to the large number of BBS genes, direct sequencing of all coding exons of these (135 exons for BBS1-12 and 23 exons for ALMS1) is not practical or cost-effective. For this reason, in collaboration with Asper Biotech (http://www.asperbio.com), we developed a BBS-ALMS1 mutation array that can be used to screen a patient sample for known mutations in 10 BBS genes and ALMS1.…”