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Ataxia-telangiectasia-like disorder in a family deficient for MRE11A, caused by a MRE11 variant

Maryam Sedghi1, Mehri Salari1, Ali-Reza Moslemi1

  • 1Medical Genetics Laboratory (M. Sedghi), Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Neurology (M. Salari), Shahid Beheshti University of Medical Science, Tehran, Iran; Department of Pathology (A.-R.M.), University of Gothenburg, Sahlgrenska University Hospital, Sweden; Kariminejad-Najmabadi Pathology & Genetics Center (A.K.), Tehran, Iran; Department of Diagnostic Genomics (M.D.), Pathwest, QEII Medical Centre; Centre for Medical Research (H.G., N.L., H.T.), The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Australia; School of Bioscience (B.O.), University of Skovde; and Division Biomedicine (H.T.), School of Health and Education, University of Skovde, Sweden.

Neurology. Genetics
|December 26, 2018
PubMed
Abstract

Insights

A rare genetic disorder, ataxia-telangiectasia-like disorder, was identified in siblings due to a specific MRE11 gene mutation. This mutation leads to MRE11A deficiency, impacting DNA repair but remaining compatible with life.

Area of Science:

  • Genetics
  • Molecular Biology
  • Neurology

Background:

  • Ataxia-telangiectasia-like disorder (ATLD) is a rare neurodegenerative disorder.
  • MRE11A is crucial for DNA double-strand break repair and forms part of the Mre11/Rad50/Nbs1 complex.

Purpose of the Study:

  • To investigate the genetic basis of ATLD in three siblings.
  • To characterize the molecular consequences of a novel MRE11 synonymous variant.

Main Methods:

  • Clinical evaluations and neurological assessments.
  • Next-generation sequencing for genetic analysis.
  • Transcript and immunohistochemistry analyses to assess MRE11A expression.

Main Results:

  • Siblings presented with characteristic ATLD features including ataxia, developmental delay, and intellectual disability.
  • A homozygous synonymous MRE11 variant (c.657C>T, p.Asn219=) affecting splicing was identified.
  • Absence of MRE11 transcripts and protein confirmed nonsense-mediated mRNA decay (NMD) and MRE11A deficiency.

Conclusions:

  • The identified MRE11A deficiency, despite its role in DNA repair, is compatible with life.
  • Synonymous variants can lead to severe genetic disorders through mechanisms like NMD.

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