Shalata Adel, Saada Ann, Mahroum Mohammed, Hadid Yarin, Furman Chaya, Shalata Zaher Eldin, Desnick Robert J, Lorber Avraham, Khoury Asaad, Higazi Adnan, Shaag Avraham, Barash Varda, Spiegel Ronen, Vlodavsky Euvgeni, Rustin Pierre, Pietrokovski Shmuel, Manov Irena, Gieger Dan, Tal Galit, Salzberg Adi, Mandel Hanna
Bnai Zion Medical Center, The Simon Winter Institute for Human Genetics, Haifa, Israel.
Seba Rihana Medical Center, Sakhnin, Israel.
Hum Genomics. 2025 Feb 28;19(1):21. doi: 10.1186/s40246-025-00723-y.
Sengers-syndrome (S.S) is a genetic disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. All reported cases were genetically caused by biallelic mutations in the AGK gene. We herein report a pathogenic variant in TIMM29 gene, encoding Tim29 protein, as a novel cause of S.S. Notably, AGK and Tim29 proteins are components of the TIM22 complex, which is responsible for importing carrier proteins into the inner mitochondrial membrane.
Clinical data of 17 consanguineous patients featuring S.S was obtained. Linkage analysis, and sequencing were used to map and identify the disease-causing gene. Tissues derived from the study participants and a Drosophila melanogaster model were used to evaluate the effects of TIMM29 variant on S.S.
The patients presented with a severe phenotype of S.S, markedly elevated serum creatine-phosphokinase, combined mitochondrial-respiratory-chain-complexes deficiency, reduced pyruvate-dehydrogenase complex activity, and reduced adenine nucleotide translocator 1 protein. Histopathological studies showed accumulation of abnormal mitochondria. Homozygosity mapping and gene sequencing revealed a biallelic variant in TIMM29 NM_138358.4:c.514T > C NP_612367.1:p.(Trp172Arg). The knockdown of the Drosophila TIMM29 orthologous gene (CG14270) recapitulated the phenotype and pathology observed in the studied cohort. We expand the clinical phenotype of S.S and provide substantial evidence supporting TIMM29 as the second causal gene of a severe type of S.S, designated as S.S- TIMM29.
The present study uncovers several biochemical differences between the two S.S types, including the hyperCPKemia being almost unique for S.S-TIMM29 cohort, the different frequency of MMRCC and PDHc deficiencies among the two S.S types. We propose to designate the S.S associated with TIMM29 homozygous variant as S.S-TIMM29.
森格斯综合征（S.S）是一种遗传性疾病，其特征为先天性白内障、肥厚型心肌病、骨骼肌病和乳酸性酸中毒。所有报道的病例均由AGK基因的双等位基因突变引起。我们在此报告了编码Tim29蛋白的TIMM29基因中的一种致病变异，这是S.S的一个新病因。值得注意的是，AGK和Tim29蛋白是TIM22复合体的组成部分，该复合体负责将载体蛋白导入线粒体内膜。
获取了17例具有S.S特征的近亲患者的临床数据。采用连锁分析和测序来定位和鉴定致病基因。使用来自研究参与者的组织和果蝇模型来评估TIMM29变异对S.S的影响。
这些患者表现出严重的S.S表型，血清肌酸磷酸激酶显著升高，合并线粒体呼吸链复合体缺陷、丙酮酸脱氢酶复合体活性降低以及腺嘌呤核苷酸转位酶1蛋白减少。组织病理学研究显示异常线粒体堆积。纯合性定位和基因测序揭示了TIMM29 NM_138358.4:c.514T＞C NP_612367.1:p.(Trp172Arg)中的双等位变异。果蝇TIMM29同源基因（CG14270）的敲低重现了在研究队列中观察到的表型和病理特征。我们扩展了S.S的临床表型，并提供了大量证据支持TIMM29作为严重型S.S（称为S.S-TIMM29）的第二个致病基因。
本研究揭示了两种S.S类型之间的一些生化差异，包括高肌酸磷酸激酶血症几乎是S.S-TIMM29队列所特有的，以及两种S.S类型中MMRCC和PDHc缺陷的不同频率。我们建议将与TIMM29纯合变异相关的S.S命名为S.S-TIMM29。
