Identification of the mutations in the tissue-nonspecific alkaline phosphatase gene in two Chinese families with hypophosphatasia.
OBJECTIVE
Hypophosphatasia is a genetic disorder characterized by defective bone and tooth mineralization and a deficiency of serum and bone alkaline phosphatase activity. To date, few studies have identified gene mutations in Chinese patients with hypophosphatasia. We sought to characterize the clinical manifestations and identify the mutations associated with the disease in Chinese hypophosphatasia patients.


METHODS
All 12 exons and the exon-intron boundaries of the ALPL gene were amplified and directly sequenced in two probands from unrelated Chinese families. The mutation sites were identified in other unaffected members of these two families and 100 healthy controls.


RESULTS
In family 1, the proband displayed one novel splice site mutation, c.298-1G>A, which consisted of a homozygous G>A transition at nucleotide 298-1 in intron 4. The proband's mother displayed the heterozygous G/A ALPL gene mutation, but her father was identified as G/G homozygous. A paternity test ruled out false paternity and therefore confirmed that this splicing mutation occurred de novo either in the paternal germline or in the early development of the patient. In family 2, the proband revealed a novel missense mutation (c.1271T>C) in exon 11, which resulted in p.Val424Ala in the mature ALPL polypeptide. Furthermore, c.298-1G>A and c.1271T>C mutations were not found in unaffected family members of these two Chinese families and 100 unrelated controls.


CONCLUSIONS
Our study shows that the novel de novo splicing mutation c.298-1G>A in intron 4 and the missense mutation c.1271T>C in exon 11 of the ALPL gene are responsible for hypophosphatasia in some Chinese patients.
Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University, Affiliated Sixth People's Hospital, PR China.
Hao
H
Zhang
Yao-Hua
YH
Ke
Chun
C
Wang
Hua
H
Yue
Wei-Wei
WW
Hu
Jie-Mei
JM
Gu
Zhen-Lin
ZL
Zhang
D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000235:genetics*; D044466:Asian People; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D050723:Fractures, Bone / Q000000981:diagnostic imaging / Q000209:etiology; D056726:Genetic Association Studies; D006801:Humans; D007014:Hypophosphatasia / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017354:Point Mutation; D022821:RNA Splice Sites / Q000235:genetics; D011859:Radiography; D055815:Young Adult
D022821:RNA Splice Sites; C548267:ALPL protein, human; D000469:Alkaline Phosphatase