P.9.5 A novel NEFL gene mutation is identified in a family diagnosed with Nemaline Myopathy
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- 作者：P.B. Agrawal ; M. Joshi ; N. Marinakis ; P.D. Ciarlini ; K. Schmitz-Abe ; K. Markianos ; U. De Girolami ; A.H. Beggs
- 刊名：Neuromuscular Disorders
- 出版年：2013
- 出版时间：October, 2013
- 年：2013
- 卷：23
- 期：9-10
- 页码：784-785
- 全文大小：58 K
文摘
We describe a family of four members (a mother and her three sons) diagnosed with a skeletal muscle disease with biopsy findings consistent with nemaline myopathy (NM) in two, one with non-specific myopathy and one with neurogenic atrophy and myopathic features. Interestingly, some of the clinico-pathological findings were consistent with involvement of the peripheral nerves. Sanger sequencing did not identify a pathogenic mutation in genes associated with NM. Given the atypical presentation not attributable to a known NM gene, linkage analysis was performed on DNA samples from the four affected members along with whole genome sequencing (WGS) on mother¡¯s DNA (proband). On bioinformatic analysis, she was identified to carry a heterozygous mutation c.1261C>T in the NEFL gene predicted to cause premature termination of the transcript and a truncated neurofilament light polypeptide protein (p.R421X). This mutation was not present in dbSNP Build 137 or Exome variant server, Washington University, and it was confirmed to be present in all the four affected members of the family by Sanger sequencing. Further, Autosomal dominant mutations in NEFL are associated with Charcot-Marie-Tooth (CMT) disease, subtypes CMT2E/CMT1F. Most of the pathogenic NEFL mutations are missense changes postulated to cause dominant negative effects. Quantitative real-time PCR was performed on cDNA, extracted from muscle samples from an affected family member and an age-matched control, and the mutant transcript was found to be stable. We hypothesize that the mutant transcript does not undergo nonsense-mediated decay, thereby encoding a truncated protein that interferes with the function of the wild type NEFL protein. Further work is underway to understand the molecular basis of the disease. This finding further expands the spectrum of NEFL mutation-associated phenotypes to NM.