MRE11 – Ataxia-Telangiectasia-Like Disorder 1

Bi-allelic MRE11 variants have been reported in one unrelated patient with autosomal recessive ataxia-telangiectasia-like disorder 1 (ATLD1), featuring progressive cerebellar ataxia, dysarthria and cervical and facial dystonia but lacking oculomotor apraxia. Exome sequencing identified two compound heterozygous alleles, c.1090C>T (p.Arg364Ter) and c.77T>C (p.Met26Thr), segregating in trans in a 45-year-old woman (1 proband) (PMID:37808486). ATLD1 is caused by hypomorphic loss of MRE11 nuclease function leading to impaired DNA double-strand break repair, concordant with yeast phosphoesterase motif mutants that abrogate DSB repair and ionizing radiation resistance (PMID:9755192, PMID:9871118). Functional assays in Saccharomyces cerevisiae confirm that loss of Mre11 nuclease or complex stability mimics null phenotypes with IR sensitivity, hyperrecombination and defective DSB processing. No additional human segregation or family studies have been published. This limited clinical evidence, coupled with robust model organism data, supports the pathogenicity of bi-allelic MRE11 variants in ATLD1. Clinical sequencing of MRE11 is advisable in early-onset AR cerebellar ataxia with radiation hypersensitivity. Key Take-home: Biallelic MRE11 loss-of-function variants cause ATLD1; include MRE11 testing in the differential diagnosis of autosomal recessive ataxia.

References

• Frontiers in neurology • 2023 • Cervical dystonia and no oculomotor apraxia as new manifestation of ataxia-telangiectasia-like disorder 1 - case report and review of the literature. PMID:37808486
• Genetics • 1998 • Alteration of N-terminal phosphoesterase signature motifs inactivates Saccharomyces cerevisiae Mre11. PMID:9755192
• Current genetics • 1998 • Molecular cloning and genetic characterization of the Saccharomyces cerevisiae NGS1/MRE11 gene. PMID:9871118

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