title: A defect in the TUSC3 gene is associated with autosomal recessive mental retardation.
abstract: Recent studies have shown that autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to believe that the number of underlying gene defects goes into the thousands. To date, however, only four genes have been implicated in nonsyndromic ARMR (NS-ARMR): PRSS12 (neurotrypsin), CRBN (cereblon), CC2D1A, and GRIK2. As part of an ongoing systematic study aiming to identify ARMR genes, we investigated a large consanguineous family comprising seven patients with nonsyndromic ARMR in four sibships. Genome-wide SNP typing enabled us to map the relevant genetic defect to a 4.6 Mbp interval on chromosome 8. Haplotype analyses and copy-number studies led to the identification of a homozygous deletion partly removing TUSC3 (N33) in all patients. All obligate carriers of this family were heterozygous, but none of 192 unrelated healthy individuals from the same population carried this deletion. We excluded other disease-causing mutations in the coding regions of all genes within the linkage interval by sequencing; moreover, we verified the complete absence of a functional TUSC3 transcript in all patients through RT-PCR. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltransferase complex that catalyzes a pivotal step in the protein N-glycosylation process. Our data suggest that in contrast to other genetic defects of glycosylation, inactivation of TUSC3 causes nonsyndromic MR, a conclusion that is supported by a separate report in this issue of AJHG. TUSC3 is only the fifth gene implicated in NS-ARMR and the first for which mutations have been reported in more than one family.
authors.affiliation: Max Planck Institute for Molecular Genetics, D-14195 Berlin, Germany.
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
authors.forename: Valeh
authors.initials: V
authors.lastname: Hadavi
authors.forename: Haleh
authors.initials: H
authors.lastname: Habibi
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.forename: Roxana
authors.initials: R
authors.lastname: Kariminejad
authors.forename: Farkhondeh
authors.initials: F
authors.lastname: Behjati
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Hans Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Andreas Walter
authors.initials: AW
authors.lastname: Kuss
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D006031:Glycosylation; D006602:Hexosyltransferases / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C524338:TUSC3 protein, human; D025521:Tumor Suppressor Proteins; D006602:Hexosyltransferases; C025620:dolichyl-diphosphooligosaccharide - protein glycotransferase