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Disease-Causing Missense Mutations in Human DNA Helicase Disorders

机译：疾病引起人体DNA氦酸酶疾病中的致畸突变

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Helicases have important roles in nucleic acid metabolism, and their prominence is marked by the discovery of genetic disorders arising from disease-causing mutations. Missense mutations can yield unique insight to molecular functions and basis for disease pathology. XPB or XPD missense mutations lead to Xeroderma pigmentosum, Cockayne’s syndrome, Trichothiodystrophy, or COFS syndrome, suggesting that DNA repair and transcription defects are responsible for clinical heterogeneity. Complex phenotypes are also observed for RECQL4 helicase mutations responsible for Rothmund-Thomson syndrome, Baller-Gerold syndrome, or RAPADILINO. Bloom’s syndrome causing missense mutations are found in the conserved helicase and RecQ C-terminal domain of BLM that interfere with helicase function. Although rare, patient-derived missense mutations in the exonuclease or helicase domain of Werner syndrome protein exist. Characterization of WRN separation-of-function mutants may provide insight to catalytic requirements for suppression of phenotypes associated with the premature aging disorder. Characterized FANCJ missense mutations associated with breast cancer or Fanconi anemia interfere with FANCJ helicase activity required for DNA repair and the replication stress response. For example, a FA patient-derived mutation in the FANCJ Iron-Sulfur domain was shown to uncouple its ATPase and translocase activity from DNA unwinding. Mutations in DDX11 (ChlR1) are responsible for Warsaw Breakage syndrome, a recently discovered autosomal recessive cohesinopathy. Ongoing and future studies will address clinically relevant helicase mutations and polymorphisms, including those that interfere with key protein interactions or exert dominant negative phenotypes (e.g., certain mutant alleles of Twinkle mitochondrial DNA helicase). Chemical rescue may be an approach to restore helicase activity in loss-of-function helicase disorders. Genetic and biochemical analyses of disease-causing missense mutations in human helicase disorders have led to new insights to the molecular defects underlying aberrant cellular and clinical phenotypes.
机译：解旋酶在核酸代谢中具有重要作用，其突出之处是发现了由致病突变引起的遗传性疾病。错义突变可以对分子功能和疾病病理学产生独特的见解。 XPB或XPD错义突变会导致色干性皮肤干燥症，Cockayne综合征，Trichothiodystrophy或COFS综合征，这表明DNA修复和转录缺陷是造成临床异质性的原因。还观察到导致Rothmund-Thomson综合征，Baller-Gerold综合征或RAPADILINO的RECQL4解旋酶突变的复杂表型。在保守的解旋酶和BLM的RecQ C末端结构域中发现了导致错义突变的Bloom综合征，它们干扰了解旋酶的功能。尽管很少见，但在Werner综合征蛋白的核酸外切酶或解旋酶域中存在患者来源的错义突变。 WRN功能分离突变体的表征可能为抑制与过早衰老相关的表型的催化需求提供见识。与乳腺癌或范可尼贫血相关的特征性FANCJ错义突变会干扰DNA修复和复制应激反应所需的FANCJ解旋酶活性。例如，FANCJ铁-硫结构域中来自FA患者的突变显示出它的ATPase和translocase活性与DNA解链无关。 DDX11（ChlR1）中的突变与华沙断裂综合征有关，华沙断裂综合征是一种最近发现的常染色体隐性粘膜病变。正在进行的和将来的研究将解决与临床有关的解旋酶突变和多态性，包括那些干扰关键蛋白质相互作用或发挥显性负表型的突变和多态性（例如，Twinkle线粒体DNA解旋酶的某些突变等位基因）。化学挽救可能是恢复功能丧失的解旋酶疾病中解旋酶活性的一种方法。人类解旋酶疾病中引起疾病​​的错义突变的遗传和生化分析已导致对异常细胞和临床表型潜在分子缺陷的新见解。

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