Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, 145 West Changle Road, Xi'an 710032, China.
Arch Oral Biol. 2010 Dec;55(12):1017-23. doi: 10.1016/j.archoralbio.2010.08.003. Epub 2010 Sep 9.
Hypophosphatasia (HPP) is an inherited disorder characterised by defective bone and tooth mineralisation and deficient serum and bone alkaline phosphatase activity, and it results from mutations in alkaline phosphatase (ALPL) encoding tissue-nonspecific alkaline phosphatase (TNAP). The objective of the present work was to explore the correlations between genotype and phenotype in a Chinese family affected by autosomal-dominant HPP.
We examined all individuals of a HPP family by clinical and radiographic examinations as well as laboratory assays. Furthermore, a prematurely exfoliated tooth was observed histopathologically. Based on the clinical and pathological manifestations, the causative gene ALPL was selected for further analysis and screened for mutations.
The proband presented the characteristic clinical features of childhood HPP such as rachitic skeletal changes, early loss of primary teeth, and short root anomalies of the permanent teeth. Histopathological evaluation of a tooth revealed a "shell" structure, severe mineralisation defects of dentin, and an absence of cementum. The patient's mother and grandfather were clinically diagnosed with adult HPP. The family showed autosomal-dominant moderate hypophosphatasia. DNA sequencing and analysis revealed a novel missense mutation (c.251A>T) in exon4 of ALPL. This mutation (p.E84V) is located in the secondary structure of TNAP's homodimer interface, and it was predicted to have a dominant negative effect.
Our findings suggest the missense transversion (c.251A>T, p.E84V) should be responsible for the HPP phenotype in this Chinese family.
低磷酸酯酶症（HPP）是一种遗传性疾病，其特征为骨骼和牙齿矿化不良，以及血清和骨碱性磷酸酶活性降低，是由于碱性磷酸酶（ALPL）编码组织非特异性碱性磷酸酶（TNAP）的突变所致。本研究旨在探讨一个常染色体显性遗传 HPP 家系中基因型与表型的相关性。
我们通过临床和影像学检查以及实验室检测对 HPP 家系的所有个体进行了检查。此外，还观察了一颗过早脱落的牙齿的组织病理学表现。根据临床表现和病理表现，选择了致病基因 ALPL 进行进一步分析和突变筛查。
先证者表现为儿童 HPP 的典型临床特征，如佝偻病骨骼改变、乳牙早期缺失和恒牙牙根短。牙齿的组织病理学评估显示出“壳”状结构，牙本质严重矿化缺陷，以及无牙骨质。患者的母亲和祖父均被临床诊断为成人 HPP。该家系表现为常染色体显性遗传中度低磷酸酯酶症。DNA 测序和分析显示 ALPL 外显子 4 中存在一个新的错义突变（c.251A>T）。该突变（p.E84V）位于 TNAP 同源二聚体界面的二级结构中，预测具有显性负效应。
我们的研究结果表明，错义转换（c.251A>T，p.E84V）可能是导致该中国家系 HPP 表型的原因。
