Meckel Syndrome 13

A number sign (#) is used with this entry because of evidence that Meckel syndrome-13 (MKS13) and Joubert syndrome-29 (JBTS29) are caused by homozygous or compound heterozygous mutation in the TMEM107 gene (616183) on chromosome 17p13. One patient with JBTS29 has been reported.

Mutation in the TMEM107 gene can also cause OFD16 (617563).

For discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000).

For discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).

Clinical Features

Shaheen et al. (2015) reported 2 unrelated consanguineous Saudi families in which 4 infants had MKS. Features included occipital encephalocele, polydactyly, polycystic kidneys, micrognathia, contractures, and perinatal lethality.

Joubert Syndrome 29

Lambacher et al. (2016) reported a 22-year-old man from the Caribbean with Joubert syndrome. He had delayed psychomotor development, intellectual disability, ataxia, oculomotor apraxia, retinopathy, liver involvement, and cerebellar hypoplasia with the molar tooth sign on brain imaging.

Inheritance

The transmission pattern of MKS13 in the families reported by Shaheen et al. (2015) was consistent with autosomal recessive inheritance.

The transmission pattern of JBTS29 in the family reported by Lambacher et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated infants, born of consanguineous Saudi parents, with MKS13, Shaheen et al. (2015) identified a homozygous loss-of-function mutation in the TMEM107 gene (616183.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in both families; haplotype analysis indicated a founder effect. Patient cells showed a significant reduction in the number of ciliated cells compared to controls, as well as abnormal cilia that were excessively elongated with a curly pattern. Patient fibroblasts also showed suppression of SHH (600725) signaling and reduced translocation of SMO (601500) to the cilium compared to control cells. The findings, similar to those observed in mice with loss of Tmem107 function (see ANIMAL MODEL), suggested that loss of TMEM107 impairs ciliogenesis. The families were from a cohort of 25 MKS families who underwent genetic analysis.

In a man with JBTS29, Lambacher et al. (2016) identified compound heterozygous mutations in the TMEM107 gene (616183.0002 and 616183.0004). The mutations segregated with the disorder in the family. Patient fibroblasts showed reduced ciliation, and the cilia that formed were abnormally long.

Animal Model

Using a forward genetic screen, Christopher et al. (2012) created the 'schlei' mutant mouse, which exhibited preaxial polydactyly, exencephaly, and disrupted ventral neural tube patterning. The defects were consistent with defective ciliary signaling via Shh (600725). Schlei mutants had reduced numbers of cilia in limb mesenchyme and in the lumen of the neural tube. They also had bulged or curled cilia, abnormally thin cilia in the neural tube, and changes in the positions of neural progenitors, consistent with altered fields of Shh responsiveness. Schlei mutant embryos showed normal nodal cilia and normal left-right patterning, and they lacked kidney or liver cysts. Christopher et al. (2012) identified the schlei mutation as an A-to-G transition in the Tmem107 gene, resulting in the substitution of a highly conserved glutamic acid with glycine (E125G) in transmembrane domain-4. Analysis of embryos doubly mutant for schlei and various components of the Shh pathway showed that Tmem107 functioned downstream of Shh, Ptch1 (601309), and Smo (SMOH; 601500) and acted synergistically with Gli2 (165230) and Gli3 (165240) to pattern ventral and intermediate neuronal cell types. Expanded expression of the Shh targets Gli1 (GLI; 165220) and gremlin (603054) in schlei mutant limbs suggested a broadened response to Shh signaling, and the schlei mutation reduced Gli3 function to regulate digit number, but not identity.