PDF(Pubmed)
Abstract：
BACKGROUND: The MYH3-associated myosinopathies comprise a spectrum of rare neuromuscular disorders mainly characterized by distal arthrogryposis with or without other features like pterygia and vertebrae fusion. CPSKF1B (contractures, pterygia, and spondylocarpotarsal fusion syndrome1B) is the only known autosomal recessiveMYH3-associated myosinopathy so far, with no more than two dozen cases being reported.
METHODS: A boy with CPSKF1B was recruited and subjected to a comprehensive clinical and imaging evaluation. Genetic detection with whole-exome sequencing (WES) was performed on the patient and extended family members to identify the causative variation. A series of in silico and in vitro investigations were carried out to verify the pathogenicity of the two variants of the identified compound heterozygous variation.
RESULTS: The patient exhibited moderate CPSKF1B symptoms including multiarticular contractures, webbed neck, and spondylocarpotarsal fusion. WES detected a compound heterozygous MYH3 variation consisting of two variants, namely NM_002470.4: c.3377A>G; p. (E1126G) and NM_002470.4: c.5161-2A>C. It was indicated that the NM_002470.4: c.3377A>G; p. (E1126G) variant mainly impaired the local hydrogen bond formation and impacted the TGF-B pathway, while the NM_002470.4: c.5161-2A>C variant could affect the normal splicing of pre-mRNA, resulting in the appearance of multiple abnormal transcripts.
CONCLUSIONS: The findings of this study expanded the mutation spectrum of CPSKF1B, provided an important basis for the counseling of the affected family, and also laid a foundation for the functional study of MYH3 mutations.
METHODS: A boy with CPSKF1B was recruited and subjected to a comprehensive clinical and imaging evaluation. Genetic detection with whole-exome sequencing (WES) was performed on the patient and extended family members to identify the causative variation. A series of in silico and in vitro investigations were carried out to verify the pathogenicity of the two variants of the identified compound heterozygous variation.
RESULTS: The patient exhibited moderate CPSKF1B symptoms including multiarticular contractures, webbed neck, and spondylocarpotarsal fusion. WES detected a compound heterozygous MYH3 variation consisting of two variants, namely NM_002470.4: c.3377A>G; p. (E1126G) and NM_002470.4: c.5161-2A>C. It was indicated that the NM_002470.4: c.3377A>G; p. (E1126G) variant mainly impaired the local hydrogen bond formation and impacted the TGF-B pathway, while the NM_002470.4: c.5161-2A>C variant could affect the normal splicing of pre-mRNA, resulting in the appearance of multiple abnormal transcripts.
CONCLUSIONS: The findings of this study expanded the mutation spectrum of CPSKF1B, provided an important basis for the counseling of the affected family, and also laid a foundation for the functional study of MYH3 mutations.
摘要：
背景：MYH3相关的嗜酸性肌病包括一系列罕见的神经肌肉疾病，其主要特征是远端关节病，有或没有其他特征，如翼状痛和椎骨融合。CPSKF1B（挛缩，翼状突起,和脊椎腕骨融合综合征1B）是迄今为止唯一已知的常染色体直肠MYH3相关的嗜酸性肌病，报告的病例不超过两打。
方法：招募一名患有CPSKF1B的男孩，并进行全面的临床和影像学评估。对患者和扩展家庭成员进行全外显子组测序（WES）的遗传检测，以鉴定致病变异。进行了一系列计算机模拟和体外研究，以验证已鉴定的复合杂合变异的两个变异体的致病性。
结果：患者出现中度CPSKF1B症状，包括多关节挛缩，网状脖子，和脊骨融合术.WES检测到由两个变体组成的复合杂合MYH3变异，即NM_002470.4:c.3377A>G;p.(E1126G)和NM_002470.4:c.5161-2A>C.表明NM_002470.4：c.3377A>G;p。（E1126G）变体主要损害局部氢键形成并影响TGF-B途径，而NM_002470.4:c.5161-2A>C变异体可影响pre-mRNA的正常剪接,导致多个异常转录物的出现。
结论：这项研究的发现扩展了CPSKF1B的突变谱，为受影响家庭的咨询提供了重要依据，为MYH3突变的功能研究奠定了基础。
方法：招募一名患有CPSKF1B的男孩，并进行全面的临床和影像学评估。对患者和扩展家庭成员进行全外显子组测序（WES）的遗传检测，以鉴定致病变异。进行了一系列计算机模拟和体外研究，以验证已鉴定的复合杂合变异的两个变异体的致病性。
结果：患者出现中度CPSKF1B症状，包括多关节挛缩，网状脖子，和脊骨融合术.WES检测到由两个变体组成的复合杂合MYH3变异，即NM_002470.4:c.3377A>G;p.(E1126G)和NM_002470.4:c.5161-2A>C.表明NM_002470.4：c.3377A>G;p。（E1126G）变体主要损害局部氢键形成并影响TGF-B途径，而NM_002470.4:c.5161-2A>C变异体可影响pre-mRNA的正常剪接,导致多个异常转录物的出现。
结论：这项研究的发现扩展了CPSKF1B的突变谱，为受影响家庭的咨询提供了重要依据，为MYH3突变的功能研究奠定了基础。
