title: Clinical, pathological and genetic evaluations of Chinese patients with autosomal-dominant hypophosphatasia.
abstract: 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.
authors.affiliation: Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, 145 West Changle Road, Xi'an 710032, China.
authors.forename: Ke-wen
authors.initials: KW
authors.lastname: Wei
authors.forename: Kun
authors.initials: K
authors.lastname: Xuan
authors.forename: Yan-li
authors.initials: YL
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Kun
authors.initials: K
authors.lastname: Ji
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Shigeru
authors.initials: S
authors.lastname: Watanabe
authors.forename: Koji
authors.initials: K
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Ojihara
mesh_terms: 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
chemical_list: D018698:Glutamic Acid; C548267:ALPL protein, human; D000469:Alkaline Phosphatase; D014633:Valine; D000225:Adenine; D013941:Thymine