Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships
Clinical spectrum of BCS1L Mitopathies and their underlying structural relationships
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DOI：
10.1002/ajmg.a.61019
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发表时间：
2019-03-01
影响因子：
2
通讯作者：
Mark, Paul R.
中科院分区：
文献类型：
--
作者：
Baker, Rachael A.;Priestley, Jessica R. C.;Mark, Paul R.
分离的复合物III缺陷最常见的原因是核编码atp酶BCS1L的突变。疾病表型多种多样，轻如Bjornstad综合征，表现为曲毛和感音神经性听力丧失，重如GRACILE综合征，表现为生长受限、氨基酸尿症、胆汁淤积、铁超载、乳酸性酸中毒和早期死亡。BCS1L突变还与未定义的复合物III缺陷有关，这是一种异质性疾病，通常涉及低出生体重、肾脏和肝脏病变、张力低下和发育迟缓。我们分析了所有已发表的BCS1L突变病例，并模拟了BCS1L蛋白的三级和四级结构，以绘制致病BCS1L突变的位置。我们表明，高阶结构分析可用于理解在具有新型复合杂合c.550C . > . T的患者中观察到的表型。Arg184Cys)和c.838C . >T(p。Leu280Phe)突变。更广泛地说，高阶结构分析揭示了中间复合物III缺陷类别内的基因型-表型关系，有助于理解观察到的表型谱。我们建议改变命名法，将中间表型统一为“BCS1L有丝分裂病”。在BCS1L的三级和四级结构中，这些BCS1L有丝分裂病的基因型-表型相关模式是显而易见的。
The most frequent cause of isolated complex III deficits is mutations to the nuclear-encoded ATPase BCS1L. Disease phenotypes are varied and can be as mild as Bjornstad syndrome, characterized by pili torti and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. BCS1L mutations are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving low birth weight, renal and hepatic pathologies, hypotonia, and developmental delays. We analyzed all published patient cases of mutations to BCS1L and modeled the tertiary and quaternary structure of the BCS1L protein to map the location of disease-causing BCS1L mutations. We show that higher order structural analysis can be used to understand the phenotype observed in a patient with the novel compound heterozygous c.550C>T(p.Arg184Cys) and c.838C>T(p.Leu280Phe) mutations. More broadly, higher order structural analysis reveals genotype-phenotype relationships within the intermediate complex III deficiency category that help to make sense of the spectrum of observed phenotypes. We propose a change in nomenclature that unifies the intermediate phenotype under "BCS1L Mitopathies". Patterns in genotype-phenotype correlations within these BCS1L Mitopathies are evident in the context of the tertiary and quaternary structure of BCS1L.