Clinical, pathological and genetic evaluations of Chinese patients with autosomal-dominant hypophosphatasia.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Our findings suggest the missense transversion (c.251A>T, p.E84V) should be responsible for the HPP phenotype in this Chinese family.
Wei
Ke-wen
KW
Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, 145 West Changle Road, Xi'an 710032, China.
Xuan
Kun
K
Liu
Yan-li
YL
Fang
Jun
J
Ji
Kun
K
Wang
Xi
X
Jin
Yan
Y
Watanabe
Shigeru
S
Watanabe
Koji
K
Ojihara
Takashi
T
D000225:Adenine; D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000235:genetics*; D002648:Child; D002681:China; D003739:Dental Cementum / Q000002:abnormalities; D003804:Dentin / Q000002:abnormalities; D005091:Exons / Q000235:genetics; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D005838:Genotype; D018698:Glutamic Acid / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007014:Hypophosphatasia / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D013941:Thymine; D014080:Tooth Exfoliation / Q000473:pathology; D014094:Tooth, Deciduous / Q000473:pathology; D014633:Valine / Q000235:genetics
D018698:Glutamic Acid; C548267:ALPL protein, human; D000469:Alkaline Phosphatase; D014633:Valine; D000225:Adenine; D013941:Thymine