Mental Retardation, Enteropathy, Deafness, Peripheral Neuropathy, Ichthyosis, And Keratoderma

A number sign (#) is used with this entry because of evidence that mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (MEDNIK) is caused by homozygous mutation in the AP1S1 gene (603531) on chromosome 7q22.

Description

MEDNIK is a severe multisystem disorder characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma. It shows phenotypic similarities to CEDNIK (609528) (summary by Montpetit et al., 2008).

Clinical Features

Erythrokeratodermia variabilis (EKV; 133200) is a congenital disorder of the skin that causes hyperkeratosis and red patches of variable sizes, shapes, and duration. In 5 children from 3 families originating from the Kamouraska region of the province of Quebec, Saba et al. (2005) described an atypical form of erythrokeratodermia variabilis, designated erythrokeratodermia variabilis-3 (Kamouraska type) and symbolized EKV3. This form was similar to a disorder previously described by Beare et al. (1972) and included sensorineural deafness, peripheral neuropathy, and psychomotor retardation; however, in addition to these symptoms, the Kamouraska patients had congenital diarrhea, an elevation of very long chain fatty acids (VLCFAs), and a recessive mode of inheritance. Two of the children died at an early age from severe congenital diarrhea.

Montpetit et al. (2008) restudied the patients reported by Saba et al. (2005) and identified another family from Quebec with the disorder. Features included high forehead with upslanting palpebral fissures, congenital sensorineural deafness, psychomotor retardation and mental retardation, peripheral neuropathy, hypotonia, and ichthyosiform erythroderma. Gastrointestinal problems included severe diarrhea, resulting in death in infancy in 4 patients, hepatic fibrosis, cirrhosis, and cholestasis. Two patients had cataracts.

Inheritance

The transmission pattern of MEDNIK in the families reported by Saba et al. (2005) and Montpetit et al. (2008) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping, Saba et al. (2005) excluded GJB3 (603324) on chromosome 1 as a candidate gene for EKV3; the same approach identified a large region on chromosome 7 that was identical by descent in all affected individuals but not in an unaffected first-degree relative. The assignment was narrowed to a 6.8-Mb region of chromosome 7q22 containing approximately 100 genes, 1 of which was CX31.3 (GJC3; 611925). Sequencing of the 2 known coding exons of the GJC3 gene revealed no mutations.

Montpetit et al. (2008) identified another family from Quebec with a phenotype similar to that described by Saba et al. (2005). Linkage analysis refined the critical region to 5.3 Mb between D7S2539 and D7S518.

Molecular Genetics

In affected members from 4 families with MEDNIK, Montpetit et al. (2008) identified the same homozygous splice site mutation in the AP1S1 gene (603531.0001). The mutation was identified by linkage analysis followed by candidate gene sequencing. The mutation was predicted to result in a truncated protein with loss of function, but a small amount of an AP1S1 protein with an in-frame deletion was also produced, which may have contributed some residual activity. Knockdown of the Ap1s1 gene in zebrafish resulted in skin and neurologic defects. The AP1S1 gene is involved in protein trafficking between organelles.

Population Genetics

All 3 families with MEDNIK reported by Saba et al. (2005) were likely to share common ancestors, as they lived in a relatively isolated population descended from founders of French origin who settled south of the St. Lawrence downstream of Quebec City in the 17th and 18th centuries.

History

See 606945.0025 for a deletion of the promoter and exon 1 of the LDLR gene causing a form of familial hypercholesterolemia called French Canadian-1, which has been identified in individuals living in the Kamouraska region of the province of Quebec.