Mental Retardation, Autosomal Recessive 12

A number sign (#) is used with this entry because autosomal recessive nonsyndromic mental retardation-12 (MRT12) can be caused by homozygous mutation in the ST3GAL3 gene (606494) on chromosome 1p34.

Clinical Features

Najmabadi et al. (2007) and Hu et al. (2011) reported 2 unrelated consanguineous Iranian families with nonsyndromic mild to moderate mental retardation.

Mapping

Najmabadi et al. (2007) reported a large consanguineous Iranian family in which 8 individuals had nonsyndromic mild mental retardation. Linkage analysis identified a candidate locus on chromosome 1p34-p33 with a maximum lod score of 7.2. Haplotype analysis delineated a 9.4-Mb candidate region between rs514262 and rs953070.

Molecular Genetics

In affected members of 2 unrelated consanguineous Iranian families with autosomal recessive nonsyndromic mental retardation, including the one reported by Najmabadi et al. (2007), Hu et al. (2011) used linkage analysis, chromosome sorting, and next-generation sequencing and identified 2 different homozygous mutations in the ST3GAL3 gene (A13D, 606494.0001 and D370Y, 606494.0002, respectively). Neither mutation affected the highly conserved sialyl motifs, but rather affected the N-terminal transmembrane domain and C-terminal catalytic domain, respectively. In vitro functional expression studies showed that the mutant proteins were mislocalized to the endoplasmic reticulum and that 1 (D370Y) had loss of catalytic activity. The findings demonstrated a link between the glycoprotein complex, sialyltransferase activity, and higher cognitive functioning.

Nomenclature

Although Najmabadi et al. (2007) referred to this locus as 'MRT4,' that designation had already been used by Uyguner et al. (2007) to refer to a locus on chromosome 1p21.1-p13.3 (MRT4; 611107). Thus, the locus described here is referred to as MRT12.