Scholarlink

<p>We report the case of a Spanish female patient with progressive myopathy and severe muscle atrophy, intellectual delay, absence of expressive language development, overweight, and mitochondrial abnormalities. Whole-exome sequencing uncovered three heterozygous <i>CHKB</i> variants in the patient, one from the paternal allele and two from de maternal allele (NC_000022.11(NM_005198.5): c. [581G &gt; A];[843&#xa0;T &gt; C;1031 + 3G &gt; C]). This gene encodes the Choline/ethanolamine kinase (CHKB) protein, which catalyzes the first step of phosphatidylcholine biosynthesis. Pathogenic CHKB variants have been associated with megaconial congenital muscular dystrophy (MDCMC). In order to assess the pathogenicity of these variants, expression experiments of RNA for <i>CHKB</i> were carried out by RT-PCR from lymphocytes. The c.581G &gt; A variant, instead to produce a missense change (p.Arg194Gln), induces an aberrant splicing event resulting in the deletion of exon 4 (<i>V1</i> and <i>V2</i>: r.448_581del). On the other hand, the other two variants (c.843&#xa0;T &gt; C (p.Phe281 =) and c.1031 + 3G &gt; C splice site variant) induces five alternative splicing events by altering the splice sites of exons 8 and 9 (<i>V3</i>: r.928_1031del, <i>V4</i>: r.970_1033del, <i>V5</i>: r.1026_1033del, <i>V6</i>: r.820_1032del and <i>V7</i>: r.819_927del). In all cases, the predicted codified proteins are truncated in carboxy-terminus, affecting to important domains of the protein or are likely to be degraded by NMD. In conclusion, we describe for the first time the pathological mechanism of the c.581G &gt; A variant, show that c.843&#xa0;T &gt; C (synonymous variant) might be responsible for the exon 8 skipping, and confirm that c.1031 + 3G &gt; C induces differential splicing as previously shown. Consequently, our findings provide additional functional evidences associated with <i>CHKB</i> variants.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Alternative splicing events of three rare variants in CHKB gene causing megaconial congenital dystrophy

  • 期刊论文

  • 发表日期：

    2025年9月30日

查看全文
  • Francisco Javier Cotrina-Vinagre,
  • María Elena Rodríguez-García,
  • María Martín-Cazaña,
  • Agustín Cárdenas Del Carre,
  • Montserrat Morales-Conejo,
  • Elena Martín-Hernández,
  • Francisco Martínez-Azorín

摘要

We report the case of a Spanish female patient with progressive myopathy and severe muscle atrophy, intellectual delay, absence of expressive language development, overweight, and mitochondrial abnormalities. Whole-exome sequencing uncovered three heterozygous CHKB variants in the patient, one from the paternal allele and two from de maternal allele (NC_000022.11(NM_005198.5): c. [581G > A];[843 T > C;1031 + 3G > C]). This gene encodes the Choline/ethanolamine kinase (CHKB) protein, which catalyzes the first step of phosphatidylcholine biosynthesis. Pathogenic CHKB variants have been associated with megaconial congenital muscular dystrophy (MDCMC). In order to assess the pathogenicity of these variants, expression experiments of RNA for CHKB were carried out by RT-PCR from lymphocytes. The c.581G > A variant, instead to produce a missense change (p.Arg194Gln), induces an aberrant splicing event resulting in the deletion of exon 4 (V1 and V2: r.448_581del). On the other hand, the other two variants (c.843 T > C (p.Phe281 =) and c.1031 + 3G > C splice site variant) induces five alternative splicing events by altering the splice sites of exons 8 and 9 (V3: r.928_1031del, V4: r.970_1033del, V5: r.1026_1033del, V6: r.820_1032del and V7: r.819_927del). In all cases, the predicted codified proteins are truncated in carboxy-terminus, affecting to important domains of the protein or are likely to be degraded by NMD. In conclusion, we describe for the first time the pathological mechanism of the c.581G > A variant, show that c.843 T > C (synonymous variant) might be responsible for the exon 8 skipping, and confirm that c.1031 + 3G > C induces differential splicing as previously shown. Consequently, our findings provide additional functional evidences associated with CHKB variants.