Alopecia-Mental Retardation Syndrome 1

A number sign (#) is used with this entry because of evidence that alopecia-mental retardation syndrome-1 (APMR1) is caused by homozygous mutation in the AHSG gene (138680) on chromosome 3q27. One such family has been reported.

Description

Alopecia-mental retardation syndrome (APMR) is a rare autosomal recessive disorder in which affected individuals show loss of hair on the scalp, absence of eyebrows, eyelashes, and axillary and pubic hair, and mild to severe mental retardation (summary by Wali et al., 2007).

Genetic Heterogeneity of Alopecia-Mental Retardation Syndrome

Loci for alopecia-mental retardation syndrome have been mapped to chromosome 3q26.2-q26.31 (APMR2; 610422) and chromosome 18q11.2-q12.2 (APMR3; 613930).

Clinical Features

Baraitser et al. (1983) reported the combination of alopecia from birth and mental retardation in 3 cousins, each in a different sibship of an inbred Middle Eastern family. The alopecia was total and involved all areas of normal hair growth. Mental retardation was severe. A similar condition was described by Perniola et al. (1980) in 2 sibs of consanguineous parents. Both sibs were deaf. Benke and Hajianpour (1985) described an inbred Pakistani family in which 3 consanguineous couples had a child with this combination. Hearing, teeth, nails, bone x-rays, and sweating were normal and the patients were not dysmorphic. The Amish hair-brain syndrome (234050) has mild mental retardation and associated short stature; the affected persons have hair which is brittle and falls out.

Reza Sailani et al. (2017) reported a large consanguineous Iranian family in which 8 individuals spanning 4 generations had APMR. Specific clinical details were not provided, but all affected individuals had alopecia and intellectual disability with an IQ ranging from 40 to 54.

Mapping

John et al. (2006) ascertained a large consanguineous kindred from a remote region in Pakistan with multiple individuals affected by alopecia and severe mental retardation. A genomewide scan mapped the disease locus to 3q26.33-q27.3. A maximum 2-point lod score of 3.05 (theta = 0.0) was obtained at marker D3S3583.

Molecular Genetics

In 7 affected members of a large consanguineous Iranian family with APMR1, Reza Sailani et al. (2017) identified a homozygous missense mutation in the AHSG gene (R317H; 138680.0004). The mutation occurred at a highly conserved residue in the propeptide within a phosphorylation motif that is proteolytically processed posttranslationally to yield the mature protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The findings were also confirmed by linkage analysis in the family. The mutation was predicted to alter protein phosphorylation, and Western blot analysis and immunoprecipitation studies of serum showed that those with the homozygous mutation had an altered AHSG protein size, whereas those who were heterozygous carriers of the mutation had only a single normal protein band. Reza Sailani et al. (2017) speculated that the R317H mutation would disrupt phosphorylation or glycosylation sites needed for proper protein function.