Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
J Clin Endocrinol Metab. 2023 Mar 10;108(4):791-801. doi: 10.1210/clinem/dgac640.
Hereditary hypophosphatemic rickets (HR) consists of a group of inherited hypophosphatemia due to mutations of different genes, which need genetic analysis to make a differential diagnosis. Among them, autosomal recessive hypophosphatemic rickets type 1 (ARHR1), caused by a homozygous mutation of dentin matrix protein 1 (DMP1), is extremely rare, with only 30 reported patients. To date, there has been no case with compound heterozygous DMP1 mutations.
To report the first compound heterozygous mutations of DMP1 causing ARHR1 and confirm the effect of the mutation on DMP1 protein.
We report the clinical features of a Chinese patient with HR. Whole-exome sequencing (WES) was performed on the proband. Then, Cytoscan HD array, Sanger sequencing, and genomic quantitative PCR (qPCR) were used to confirm the mutations. A cell experiment was conducted to explore the effect of the mutation.
The proband is a 4-year-old boy, who developed genu varum when he was able to walk at age 1 year and tooth loss after a mild hit at age 3.5 years. Physical examination, biochemical measurement, and imaging finding indicated HR. Family history was negative. WES performed on the proband revealed a novel start codon mutation (c.1A > T, p.Met1Leu) in DMP1 and a large deletion involving most of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family gene, including DSPP, DMP1, IBSP, and MEPE. The novel paternally inherited start codon mutation, which resulted in decreased expression of DMP1 protein with smaller molecular weight and cleavage defect, was confirmed by Sanger sequencing. The maternally inherited deletion was validated by Cytoscan and qPCR, and the breakpoint was finally identified by long-range PCR and Sanger sequencing. Manifestation of dentin dysplasia (DD) or dentinogenesis imperfecta (DGI) caused by DSPP mutations was absent in the patient and his mother, confirming that haploinsufficiency could not lead to DD or DGI.
We report for the first time compound heterozygous DMP1 mutations consisting of a large deletion and a novel start codon mutation (c.1A > T, p.Met1Leu) in a Chinese patient with ARHR1.
遗传性低血磷性佝偻病（HR）由一组不同基因突变引起的遗传性低血磷症组成，需要进行基因分析以做出鉴别诊断。其中，常染色体隐性低血磷性佝偻病 1 型（ARHR1）由牙本质基质蛋白 1（DMP1）的纯合突变引起，极为罕见，仅有 30 例报道。迄今为止，尚无复合杂合 DMP1 突变的病例。
报道首例由 DMP1 复合杂合突变引起的 ARHR1，并证实该突变对 DMP1 蛋白的影响。
我们报告了一名 HR 中国患者的临床特征。对先证者进行全外显子组测序（WES）。然后，使用 Cytoscan HD 阵列、Sanger 测序和基因组定量 PCR（qPCR）来确认突变。进行细胞实验以探讨突变的影响。
先证者为 4 岁男孩，1 岁能走路时出现膝内翻，3.5 岁时轻度撞击后牙齿脱落。体格检查、生化测量和影像学发现提示 HR。家族史阴性。对先证者进行 WES 显示 DMP1 中存在一个新的起始密码子突变（c.1A>T，p.Met1Leu）和一个包含大多数小整合素结合配体 N-连接糖蛋白（SIBLING）家族基因的大片段缺失，包括 DSPP、DMP1、IBSP 和 MEPE。通过 Sanger 测序证实了新的父系遗传起始密码子突变，导致 DMP1 蛋白表达减少，分子量更小，且存在切割缺陷。通过 Cytoscan 和 qPCR 验证了母系遗传缺失，通过长距离 PCR 和 Sanger 测序最终确定了断点。该患者及其母亲均不存在 DSPP 突变引起的牙本质发育不良（DD）或牙本质生成不全（DGI）表现，证实了单倍不足不能导致 DD 或 DGI。
我们首次报道了一名 ARHR1 中国患者存在由大片段缺失和新的起始密码子突变（c.1A>T，p.Met1Leu）组成的 DMP1 复合杂合突变。
