一个因MRE11A基因变异而缺乏该基因的家族中的共济失调毛细血管扩张样病症。
Ataxia-telangiectasia-like disorder in a family deficient for MRE11A, caused by a variant.
作者信息
Sedghi Maryam, Salari Mehri, Moslemi Ali-Reza, Kariminejad Ariana, Davis Mark, Goullée Hayley, Olsson Björn, Laing Nigel, Tajsharghi Homa
机构信息
Medical 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.
出版信息
Neurol Genet. 2018 Dec 3;4(6):e295. doi: 10.1212/NXG.0000000000000295. eCollection 2018 Dec.
OBJECTIVE
We report 3 siblings with the characteristic features of ataxia-telangiectasia-like disorder associated with a homozygous synonymous variant causing nonsense-mediated mRNA decay (NMD) and MRE11A deficiency.
METHODS
Clinical assessments, next-generation sequencing, transcript and immunohistochemistry analyses were performed.
RESULTS
The patients presented with poor balance, developmental delay during the first year of age, and suffered from intellectual disability from early childhood. They showed oculomotor apraxia, slurred and explosive speech, limb and gait ataxia, exaggerated deep tendon reflex, dystonic posture, and mirror movement in their hands. They developed mild cognitive abilities. Brain MRI in the index case revealed cerebellar atrophy. Next-generation sequencing revealed a homozygous synonymous variant in (c.657C>T, p.Asn219=) that we show affects splicing. A complete absence of transcripts in the index case suggested NMD and immunohistochemistry confirmed the absence of a stable protein.
CONCLUSIONS
Despite the critical role of MRE11A in double-strand break repair and its contribution to the Mre11/Rad50/Nbs1 complex, the absence of MRE11A is compatible with life.
目的
我们报告了3名患有共济失调-毛细血管扩张样疾病特征的同胞，他们存在一个导致无义介导的mRNA降解（NMD）和MRE11A缺陷的纯合同义变异。
方法
进行了临床评估、二代测序、转录本和免疫组化分析。
结果
患者表现为平衡能力差、1岁以内发育迟缓，幼儿期即出现智力残疾。他们有眼球运动失用、言语含糊且急促、肢体和步态共济失调、深腱反射亢进、肌张力障碍姿势以及手部镜像运动。他们具有轻度认知能力。首例患者的脑部MRI显示小脑萎缩。二代测序揭示了（c.657C>T，p.Asn219=）中的一个纯合同义变异，我们发现该变异影响剪接。首例患者中完全不存在转录本提示存在NMD，免疫组化证实不存在稳定的蛋白质。
结论
尽管MRE11A在双链断裂修复中起关键作用且对Mre11/Rad50/Nbs1复合体有贡献，但MRE11A的缺失与生命相容。
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