Meckel Syndrome, Type 3

A number sign (#) is used with this entry because of evidence that Meckel syndrome type 3 (MKS3) is caused by homozygous or compound heterozygous mutation in the TMEM67 gene (609884) on chromosome 8q22.

Description

Meckel syndrome is an autosomal recessive pre- or perinatal lethal malformation syndrome characterized by renal cystic dysplasia and variably associated features including developmental anomalies of the central nervous system (typically occipital encephalocele), hepatic ductal dysplasia and cysts, and postaxial polydactyly (summary by Smith et al., 2006).

For a more complete phenotypic description and information on genetic heterogeneity of Meckel syndrome, see MKS1 (249000).

Clinical Features

Morgan et al. (2002) stated that comparison of the clinical features of MKS3-linked cases with reports of MKS1- and MKS2 (603194)-linked kindreds suggested that polydactyly, and possibly encephalocele, are less common in MKS3-linked families.

Consugar et al. (2007) observed that polydactyly and occipital encephalocele were less common in MKS3 compared to MKS1.

Mapping

By a genomewide linkage search using homozygosity mapping in 8 consanguineous kindreds with MKS originating from the Indian subcontinent, Morgan et al. (2002) identified an MKS locus (MKS3) on chromosome 8q24, with a maximum cumulative 2-point lod score of 3.04 at theta = 0.06 with marker D8S1179. Heterozygosity tests provided evidence of 1 unlinked family. Exclusion of this family for multipoint analysis maximized the cumulative multipoint lod score to 5.65 with marker D8S1128.

Smith et al. (2006) refined MKS3 mapping to a 12.67-Mb interval (8q21.3-q22.1) that shows homology of synteny to the Wpk locus in rat.

Molecular Genetics

Smith et al. (2006) sequenced the human ortholog of rat Wpk, TMEM67 (609884), and found different pathogenic mutations in 5 MKS3 families. Consistent with the consanguineous nature of these families, all the mutations were homozygous.

Consugar et al. (2007) identified 7 novel pathogenic mutations in the TMEM67 gene (see, e.g., 609884.0011) in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All 5 families were of European origin.

In a patient from a consanguineous family who presented with MKS3 and cerebellar heterotopia, Adams et al. (2012) identified a homozygous deletion in the C-terminal region of meckelin (609884.0025). The deletion abrogated the interaction of meckelin with filamin A (FLNA; 300017), resulting in aberrant hyperactivation of canonical Wnt signaling in patient fibroblasts compared with controls.

Heterogeneity

Shaheen et al. (2011) identified a consanguineous Arab family in whom the Meckel-Gruber syndrome phenotype mapped to the MKS3 locus but in whom no mutation in the TMEM67 gene was found.

Animal Model

The Wpk rat was originally suggested to be a model system for autosomal recessive polycystic kidney disease (see 263200) (Nauta et al., 2000), but further characterization of the phenotype demonstrated central nervous system malformations, including hypoplasia to agenesis of the corpus callosum with severe hydrocephaly (Nauta et al., 2000; Gattone et al., 2004). Smith et al. (2006) refined the mapping of the Wpk locus and analyzed the annotated genomic sequence, showing that the critical region contained 13 genes conserved in the syntenic mouse and human regions. Sequence analysis of a novel gene in the mutant rat showed a nonconservative substitution, P394L, in exon 12 that was not present in the parental Wistar strain.