与复杂性遗传性痉挛性截瘫相关的纯合子错义突变
homozygous missense mutation associated with complicated hereditary spastic paraplegia.
作者信息
Bouwkamp Christian G, Afawi Zaid, Fattal-Valevski Aviva, Krabbendam Inge E, Rivetti Stefano, Masalha Rafik, Quadri Marialuisa, Breedveld Guido J, Mandel Hanna, Tailakh Muhammad Abu, Beverloo H Berna, Stevanin Giovanni, Brice Alexis, van IJcken Wilfred F J, Vernooij Meike W, Dolga Amalia M, de Vrij Femke M S, Bonifati Vincenzo, Kushner Steven A
机构信息
Department of Psychiatry (C.G.B., S.R., F.M.S.d.V., S.A.K.) and Department of Clinical Genetics (C.G.B., M.Q., G.J.B., H.B.B., V.B.), Erasmus MC, Rotterdam, The Netherlands; Sackler School of Medicine (Z.A., A.F.-V.), Tel-Aviv University, Ramat-Aviv; Pediatric Neurology Unit (A.F.-V.), Dana Children's Hospital, Tel-Aviv Medical Center, Israel; Department of Molecular Pharmacology (I.E.K., A.M.D.), Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands; Clalit Health Services (R.M.), Sharon-Shomron, Hadera District; Faculty of Health Science (R.M.), Ben-Gurion University of the Negev, Beer Sheva; Metabolic Disease Unit (H.M.), Meyer Children's Hospital, Rambam Health Care Campus and Technion Faculty of Medicine, Haifa; Nursing Research Unit (M.A.T.), Soroka University Medical Center and Faculty of Health Science, Ben Gurion University of the Negev, Be'er Sheva, Israel; Ecole Pratique des Hautes Etudes (G.S.), PSL Research University, Neurogenetics Laboratory; Institut du Cerveau et de la Moelle Epinière (G.S., A.B.), Sorbonne University, Pierre and Marie Curie University UMR_S1127, INSERM u1127, CNRS UMR5225, Paris, France; Center for Biomics (W.F.J.v.I.), Erasmus MC; Department of Epidemiology (M.W.V.) and Department of Radiology (M.W.V.), Erasmus MC, Rotterdam, The Netherlands.
出版信息
Neurol Genet. 2018 Mar 21;4(2):e223. doi: 10.1212/NXG.0000000000000223. eCollection 2018 Apr.
OBJECTIVE
To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP).
METHODS
Clinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP.
RESULTS
A homozygous missense mutation was identified in the gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia.
CONCLUSIONS
Our findings nominate as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.
目的
确定一个患有遗传性痉挛性截瘫（HSP）的家系的临床特征和遗传病因。
方法
对一个患有复杂HSP的近亲家系进行临床、遗传和功能分析，包括全基因组连锁分析和全外显子组测序。
结果
在该基因中鉴定出一个纯合错义突变（c.1240T>G p.Phe414Val），该突变与伴有智力残疾和小头畸形的HSP共分离。纯合携带者患者的淋巴母细胞系显示线粒体乌头酸酶活性显著降低，线粒体呼吸存在缺陷。该基因编码线粒体乌头酸酶，这是三羧酸循环中的一种关键酶。此前已发现该基因的隐性突变与小脑共济失调有关。
结论
我们的研究结果将该基因确定为常染色体隐性复杂HSP的致病基因，并为线粒体缺陷在HSP发病机制中的核心作用提供了进一步支持。
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