Spectrum ofMKS1andMKS3mutations in Meckel syndrome: a genotype-phenotype correlation

Abstract

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations (typically occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. MKS is genetically heterogeneous and three loci have been mapped respectively on 17q23 (MKS1), 11q13 (MKS2), and 8q24 (MKS3). Very recently, two genes have been identified: MKS1/FLJ20345 on 17q in Finnish kindreds, carrying the same intronic deletion, c.1408-35_c.1408-7del29, and MKS3/TMEM67 on 8q in families from Pakistan and Oman. Here we report the genotyping of the MKS1 and MKS3 genes in a large, multiethnic cohort of 120 independent cases of MKS. Our first results indicate that the MKS1 and MKS3 genes are each responsible for about 7% of MKS cases with various mutations in different populations. A strong phenotype-genotype correlation, depending on the mutated gene, was observed regarding the type of central nervous system malformation, the frequency of polydactyly, bone dysplasia, and situs inversus. The MKS1 c.1408-35_1408-7del29 intronic mutation was identified in three cases from French or English origin and dated back to 162 generations (approx. 4050 years) ago. We also identified a common MKS3 splice-site mutation, c. INTRODUCTIONMeckel syndrome (MKS; MIM# 249000) is a rare autosomal recessive lethal condition characterized by central nervous system malformations (typically occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia and ductal proliferation in the portal area of the liver (Mecke and Passarge, 1971). Other malformations frequently include microphthalmia, cleft lip and palate, bowing of long bones, heart defects, and genital anomalies, including micropenis. Complete or partial situs inversus and other laterality defects, such as dextrocardia, have been reported in some cases. MKS is genetically heterogeneous and three loci have been mapped on: 17q23 (MKS1) (Paavola, et al., 1995), 11q14 (MKS2) (Roume, et al., 1998), and 8q24 (MKS3) (Morgan, et al., 2002). Very recently, two genes have been identified: MKS1/FLJ20345 (MIM# 609883) on 17q (Kyttälä, et al., 2006) in endogamous Finnish kindreds, and MKS3/TMEM67 (MIM# 607361) on 8q (Smith, et al., 2006) in consanguineous families from Pakistan and Oman. In 26 Finnish families, the same intronic deletion, c.1408-35_1408-7del29 (called the MKS1-Fin major mutation), was found with a common founder haplotype. Comparative genomics and proteomics data have implicated MKS proteins in primary ciliary and basal body function (Kytällä, et al., 2006;Smith, et al., 2006).In order to evaluate the involvement of MKS1 and MKS3 in Meckel syndrome, and to determine phenotypegenotype correlations and the limits of the phenotypes, we sequenced and/or performed denaturing high performance liquid chromatography (dHPLC) WAVE analysis (Transgenomic Inc.) for both MKS1 and MKS3 in a large multiethnic cohort of 120 independent cases of MKS, each diagnosed by experien...

The hydrolethalus syndrome protein HYLS-1 links core centriole structure to cilia formation

“…These loci include MKS3/JBTS6 (Baala et al 2007b), NPHP1/JBTS4 (Parisi et al 2004), MKS4/NPHP6/JBTS5 (Sayer et al 2006;Valente et al 2006;Baala et al 2007a), and MKS5/NPHP8/JBTS7 (Arts et al 2007;Delous et al 2007). Notably, the genes currently identified for MeckelGruber syndrome, nephronophthisis, and Joubert syndrome are only mutated in a small percentage of affected individuals, suggesting that other loci responsible for these disorders remain to be identified (Khaddour et al 2007;Hildebrandt et al 2009). It is possible that mutations in HYLS1, distinct from the one linked to hydrolethalus syndrome, are associated with these or other ciliary disorders.…”

Meckel-Gruber Syndrome Protein MKS3 Is Required for Endoplasmic Reticulum-associated Degradation of Surfactant Protein C

“…Mutations in MKS3 are associated with a range of ciliopathies, including Joubert syndrome (34), COACH syndrome (35), and Bardet-Biedl syndrome (36), in addition to Meckel-Gruber syndrome (14,15). There are very little data regarding the effect of mutations on protein stability/function or the function of the WT protein in ciliogenesis.…”

“…Among the 50 most highly up-regulated genes in cells expressing mutant SP-C was MGC26979/TMEM67, subsequently identified as MKS3. Genotype-phenotype analyses indicated that recessive mutations at the MKS3 locus were associated with Meckel-Gruber syndrome, a lethal disease characterized by polycystic kidneys, malformations of the liver and central nervous system, and polydactyly (14,15); however, the function of MKS3 and its role in pathogenesis are not known. The link between mutant SP-C and elevated expression of MKS3 led us to test the hypothesis that MKS3 is a component of the ERAD machinery.…”

Clinical utility gene card for: Meckel syndrome

“…In addition, 17 other mutations listed so far for patients with the Meckel-Gruber phenotype (three nonsense, one missense, seven canonical splice-site mutations, four small deletions/duplications, one silent mutation, and one intronic 143-bp deletion, both leading to aberrant splicing). 3,12,13 TMEM216/MKS2: Three different mutations described so far in patients with Meckel-Gruber syndrome (one nonsense, one splicing, and one missense mutation). 6 TMEM67/MKS3: Wide mutational spectrum without significant hotspot mutation in non-isolated cohorts.…”

“…So far, 37 different mutations described in patients with the Meckel-Gruber phenotype (5 nonsense, 17 missense, 7 canonical splice-site mutations, 7 small deletions/insertions/duplications, and 1 gross deletion described at genomic DNA level encompassing exons 17-21). 3,13,14 CEP290/MKS4: Recurrent mutation c.1219_1220del p.Met407fs in several families. A total of 13 different mutations described so far in patients with the Meckel-Gruber phenotype (five nonsense, two canonical splicesite mutations, and six small deletions/insertions/duplications).…”