Department of Endocrinology, Genetics, Metabolism and Adolescent Medicine, Beijing Children's Hospital, the Capital Medical University, National Center for Children's Health, 56# Nan Lishi Rd, West District, Beijing, 100045, P. R. China.
Orphanet J Rare Dis. 2020 Jul 20;15(1):188. doi: 10.1186/s13023-020-01459-9.
Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46,XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46,XY DSD. Cases of 46,XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children's Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated.
Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.R356X, p.Q152X, and p.Q124X) and six missense (p.P334S, p.S662R, p.A421P,p.T992I, p.P542S, and p.R927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662R, and p.R927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function.
Patients with 46,XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46,XY DSD.
先前已发现类泛素结合酶样域蛋白 1（MAMLD1）是“46,XY 性发育障碍（DSD）”的致病基因。最近，关于 MAMLD1 变异在 DSD 中的致病作用存在一些争议。本研究描述了一系列临床病例，并回顾了已报道的病例，以评估 MAMLD1 变异在 46,XY DSD 患儿中的作用。我们从中国北京儿童医院（N=10）或文献检索（N=26）中招募了来自无亲缘关系的家庭的携带 MAMLD1 变异的 46,XY DSD 病例。评估了所有患者的临床表现和遗传变异。
在我们的 10 例病例中（10 例中有 8 例）和所有先前报道的病例中，最常见的表型是尿道下裂。首次观察到中枢性性早熟和孤立性小阴茎。在 10 例病例中，共发现 9 种变异，包括 3 种无义（p.R356X、p.Q152X 和 p.Q124X）和 6 种错义（p.P334S、p.S662R、p.A421P、p.T992I、p.P542S 和 p.R927L）变异。计算机分析表明，p.P334S、p.P542S、p.S662R 和 p.R927L 可能导致氨基酸链相互作用力和空间结构灵活性的急剧变化，这些变化可能影响蛋白质功能。
携带 MAMLD1 变异的 46,XY DSD 患者表现出广泛的表型，主要表现为尿道下裂。本研究报道的 6 个新变异丰富了突变数据库，有助于我们了解 46,XY DSD 的发病机制。
