Glycoside hydrolases (GHs) are found in all domains of life, and at least 87 distinct genes encoding proteins related to GHs are found in the human genome. GHs serve diverse functions from digestion of dietary polysaccharides to breakdown of intracellular oligosaccharides, glycoproteins, proteoglycans and glycolipids. Congenital disorders of GHs (CDGHs) represent more than 30 rare diseases caused by mutations in one of the GH genes. We previously used whole-exome sequencing of a homogenous Danish population of almost 2000 individuals to probe the incidence of deleterious mutations in the human glycosyltransferases (GTs) and developed a mutation map of human GT genes (GlyMAP-I). While deleterious disease-causing mutations in the GT genes were very rare, and in many cases lethal, we predicted deleterious mutations in GH genes to be less rare and less severe given the higher incidence of CDGHs reported worldwide. To probe the incidence of GH mutations, we constructed a mutation map of human GH-related genes (GlyMAP-II) using the Danish WES data, and correlating this with reported disease-causing mutations confirmed the higher prevalence of disease-causing mutations in several GH genes compared to GT genes. We identified 76 novel nonsynonymous single-nucleotide variations (nsSNVs) in 32 GH genes that have not been associated with a CDGH phenotype, and we experimentally validated two novel potentially damaging nsSNVs in the congenital sucrase-isomaltase deficiency gene, SI. Our study provides a global view of human GH genes and disease-causing mutations and serves as a discovery tool for novel damaging nsSNVs in CDGHs.

中文翻译：

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人糖苷水解酶基因的突变图谱。

糖苷水解酶 (GHs) 存在于生命的所有领域，并且在人类基因组中发现了至少 87 个不同的编码与 GHs 相关的蛋白质的基因。GH 具有多种功能，从消化膳食多糖到分解细胞内寡糖、糖蛋白、蛋白聚糖和糖脂。先天性 GHs (CDGHs) 代表 30 多种由 GH 基因突变引起的罕见疾病。我们之前使用了近 2000 个人的同质丹麦人群的全外显子组测序来探测人类糖基转移酶 (GT) 中有害突变的发生率，并开发了人类 GT 基因 (GlyMAP-I) 的突变图谱。虽然 GT 基因中有害的致病突变非常罕见，并且在许多情况下是致命的，鉴于全球报道的 CDGH 发生率较高，我们预测 GH 基因中的有害突变不太罕见且不太严重。为了探测 GH 突变的发生率，我们使用丹麦 WES 数据构建了人类 GH 相关基因 (GlyMAP-II) 的突变图，并将其与报告的致病突变相关联，证实了在几个GH 基因与 GT 基因的比较。我们在 32 个与 CDGH 表型无关的 GH 基因中鉴定了 76 个新的非同义单核苷酸变异 (nsSNV)，并且我们通过实验验证了先天性蔗糖酶-异麦芽糖酶缺乏基因 SI 中的两个新的潜在破坏性 nsSNV。我们的研究提供了人类 GH 基因和致病突变的全局视图，并作为 CDGH 中新型破坏性 nsSNV 的发现工具。