Joubert syndrome (JS) is an autosomal recessive disorder characterized by cerebellar vermis hypoplasia associated with hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The association of retinal dystrophy and renal anomalies defines JS type B. JS is a genetically heterogeneous condition with mutations in two genes, AHI1 and CEP290, identified to date. In addition, NPHP1 deletions identical to those that cause juvenile nephronophthisis have been identified in a subset of patients with a mild form of cerebellar and brainstem anomaly. Occipital encephalocele and/or polydactyly have occasionally been reported in some patients with JS, and these phenotypic features can also be observed in Meckel-Gruber syndrome (MKS). 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. Since there is obvious phenotypic overlap between JS and MKS, we hypothesized that mutations in the recently identified MKS genes, MKS1 on chromosome 17q and MKS3 on 8q, may be a cause of JS. After mutation analysis of MKS1 and MKS3 in a series of patients with JS (n=22), we identified MKS3 mutations in four patients with JS, thus defining MKS3 as the sixth JS locus (JBTS6). No MKS1 mutations were identified in this series, suggesting that the allelism is restricted to MKS3.

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...