TUSC3 – Autosomal Recessive Non-Syndromic Intellectual Disability

TUSC3 encodes a subunit of the endoplasmic reticulum–bound oligosaccharyltransferase complex required for protein N-glycosylation. Bi-allelic loss-of-function variants in TUSC3 underlie autosomal recessive non-syndromic intellectual disability (MONDO:0019502).

Clinical validity is categorized as Strong based on identification of 10 unrelated probands in two consanguineous pedigrees (3 in an Iranian family PMID:21739581; 7 in a Pakistani sibship PMID:18452889), multi-family segregation and concordant functional data.

Genetic evidence supports autosomal recessive inheritance with two distinct variant classes: a homozygous intragenic deletion partly removing TUSC3 in a large Pakistani family (PMID:18452889) and a nonsense variant c.163C>T (p.Gln55Ter) in exon 2 in an Iranian pedigree (PMID:21739581).

All affected individuals in both families were homozygous for the respective variants; obligate carriers were heterozygous, and no deletion or nonsense allele was observed in >190 ethnically matched controls (PMID:18452889; PMID:21739581).

Functional studies demonstrated complete absence of TUSC3 transcript in patient-derived cells by RT-PCR, consistent with loss of oligosaccharyltransferase function and impaired N-glycosylation (PMID:18452889).

Collectively, genetic and experimental concordance establish TUSC3 as a robust cause of autosomal recessive non-syndromic intellectual disability. This association informs molecular diagnostic testing and potential glycosylation-targeted therapies.

References

• American Journal of Human Genetics • 2008 • A defect in the TUSC3 gene is associated with autosomal recessive mental retardation. PMID:18452889
• American Journal of Medical Genetics Part A • 2011 • A novel nonsense mutation in TUSC3 is responsible for non-syndromic autosomal recessive mental retardation in a consanguineous Iranian family. PMID:21739581

Evidence Based Scoring (AI generated)