Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy.

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.

Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS; OMIM 301900) is characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not deformed ears. Previously, the gene associated with BFLS was localized to 17 Mb in Xq26-q27 (refs 2-4). We have reduced this interval to roughly 9 Mb containing more than 62 genes. Among these, a novel, widely expressed zinc-finger (plant homeodomain (PHD)-like finger) gene (PHF6) had eight different missense and truncation mutations in seven familial and two sporadic cases of BFLS. Transient transfection studies with PHF6 tagged with green fluorescent protein (GFP) showed diffuse nuclear staining with prominent nucleolar accumulation. Such localization, and the presence of two PHD-like zinc fingers, is suggestive of a role for PHF6 in transcription.

X-linked mild non-syndromic mental retardation with neuropsychiatric problems and the missense mutation A365E in PAK3.

We describe a family of 19 males in five generations with mild to borderline non-syndromic X-linked mental retardation (MRX). There were no clinical manifestations in the affected males other than mental impairment and relatively long ears, with neuropsychiatric problems in some cases. Linkage analysis carried out on part of the pedigree using 34 markers spanning the X chromosome localized the gene between DXS454 and DXS1001 in Xq23. The maximum two-point lod score was 3.21 at DXS1059. PAK3 is a known MRX gene mapping to the same region. The affected males and obligate carrier females were found to have a missense mutation c.1094C > A in exon 10 causing an A365E substitution in a highly conserved region of the protein. The C to A base change abolishes a PvuII restriction enzyme site providing the basis for a simple test, if required, for carrier detection and prenatal diagnosis in the extended family.