The prevalence of GALM mutations that cause galactosemia: A database of functionally evaluated variants
The prevalence of GALM mutations that cause galactosemia: A database of functionally evaluated variants
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DOI：
10.1016/j.ymgme.2019.01.018
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发表时间：
2019-04-01
影响因子：
3.8
通讯作者：
Kure, Shigeo
中科院分区：
文献类型：
--
作者：
Iwasawa, Shinya;Kikuchi, Atsuo;Kure, Shigeo
半乳糖血症是一种代谢紊乱，影响 β-D-半乳糖的适当代谢。 Leloir 途径的三种酶（即 GALT、GALK1 或 GALE）缺乏，分别被表征为 I、II 和 III 型半乳糖血症。最近，我们报道了一种由双等位基因 GALM 突变引起的新型半乳糖血症（IV 型半乳糖血症）。由于目前尚未建立生化诊断方法，因此基因诊断对于诊断GALM缺陷是必不可少的。鉴于在公共变异数据库中发现了 GALM 中明显的致病变异，我们推测存在尚未报道的致病变异。在本研究中，我们探索了 ExAC 数据库中常见的 67 个 GALM 变体，包括 57 个错义变体、7 个停止增益变体、2 个移码变体和 1 个剪接位点变体。我们进行了体外表达测定和酶活性测定。 66个变异中，除1个剪接位点变异外，有29个不产生或产生微弱的蛋白质表达，被判定为致病变异。此外，其余 37 个变体通过酶活性测定进行了评估。其中两个表现出酶活性轻度降低，被归类为良性。根据我们的研究，所有人群中 GALM 缺乏症的估计发病率为 1:228,411，非洲人群中为 1:10,388，日本人群中为 1:80,747。我们的 GALM 突变数据库对于 GALM 缺陷的基因诊断非常有用。
Galactosemia is a metabolic disorder that affects the appropriate metabolism of beta-D-galactose. Deficiencies in three of the enzymes of the Leloir pathway, namely, GALT, GALK1, or GALE, are characterized as type I, II, and III galactosemia, respectively. Recently, we reported a novel type of galactosemia (type IV galactosemia) due to biallelic GALM mutations. Genetic diagnosis is indispensable for diagnosing GALM deficiency because no biochemical diagnosis method has been established. Given that apparently pathogenic variants in GALM are found in public variant databases, we presumed the presence of pathogenic variants that have not been reported. In this study, we explore 67 GALM variants that are prevalent in the ExAC database, including 57 missense variants, 7 stop-gain variants, 2 frameshift variants, and 1 splice-site variant. We performed an in vitro expression assay and an enzyme activity assay. Among the 66 variants except for 1 splice-site variant, 29 produced no or faint protein expression and were judged as pathogenic variants. Furthermore, the remaining 37 variants were evaluated by enzyme activity assay. Two showed mildly reduced enzyme activity and were classified as benign. Based on our study, the estimated incidence of GALM deficiency is 1:228,411 in all populations, 1:10,388 in the African population, and 1:80,747 in the Japanese population. Our GALM mutation database is useful for the genetic diagnosis of GALM deficiency.