Summary

J Hum Genet. 2017 Feb;62(2):159-166. doi: 10.1038/jhg.2016.134. Epub 2016 Nov 10.

Missing genetic variations in GNE myopathy: rearrangement hotspots encompassing 5'UTR and founder allele.

Abstract:

GNE myopathy is an autosomal recessive distal myopathy caused by loss-of-function mutations in the GNE gene, which encodes UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE), a key enzyme in sialic-acid biosynthesis. By comprehensive screening of manifesting patients using a fine-mapped targeted next-generation sequencing (NGS), we identified copy number variations (CNVs) in 13 patients from 11 unrelated families. The nine unique CNVs largely vary in size from 0.3 to 72 kb. Over half of the cases carry different deletions spanning merely exon 2, which contains the 5' untranslated region (5'UTR) of the muscle major transcript hGNE1. Of most unique CNVs, either the telomeric or the centromeric breakpoint locates within intron 2, indicating rearrangement hotspots. Haplotype analysis suggested the existence of a founder allele with exon 2 deletion. The breakpoints for all CNVs were determined by long-range PCR and sequencing. All of the breakpoints of gross deletion/duplications reside within directly oriented pairs of Alu repeats. The results of this study firstly widen the spectra of mutations to CNVs encompassing 5'UTR, underscoring the pivotal role of the hGNE1 transcript. Alu-mediated non-recurrent CNVs may have been overlooked in a wide variety of recessive phenotypes, especially in those associated with genomic Alu-rich genes such as GNE.

日本語要旨:

DMRV患者さんの多くは、GNE遺伝子の、両方のアリルに遺伝子変異を持つことが知られていますが、通常のシークエンス法では一つしか変異が見つからないことがあります。これらの患者さんで、次世代シークエンサーを用いた詳細な解析をすることにより、もう一方のアリルに、GNE遺伝子内の大きな欠失が高率に見つかることを見いだしました。さらに興味深いことに、欠失断端の配列解析により、これらの欠失が、レトロトランスポゾン由来のAlu配列によって起きている可能性を指摘しました。Alu配列は全ゲノムの10%程度を占めるといわれておりますが、他の病気でも、ゲノム内の大きな欠失の原因となることが、報告されてきております。

PMID:  27829678

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