Familial isolated primary hyperparathyroidism/hyperparathyroidism-jaw tumour syndrome caused by germline gross deletion or point mutations of CDC73 gene in Chinese.
OBJECTIVE
Hyperparathyroidism-jaw tumour syndrome (HPT-JT) and familial isolated primary hyperparathyroidism (FIHP) are two subtypes of familial primary hyperparathyroidism, which are rarely reported in Chinese population. Here, we reported three FIHP families and one HPT-JT family with long-term follow-up and genetic analysis.


METHODS
A total of 22 patients, from four FIHP/HPT-JT families of Chinese descent, were recruited and genomic DNA was extracted from their peripheral blood lymphocytes. Direct sequencing for MEN1, CDC73, CASR gene was conducted. Reverse transcription PCR (RT-PCR) and quantitative real-time PCR (qRT-PCR) were used to study the effect of splice site mutations and gross deletion mutations. Immunohistochemistry was performed to analyse parafibromin expression in parathyroid tumours. Genotype-phenotype correlations were assessed through clinical characteristics and long-term follow-up data.


RESULTS
Genetic analysis revealed four CDC73 germline mutations that were responsible for the four kindreds, including two novel point mutation (c.157 G>T and IVS3+1 G>A), one recurrent point mutation (c.664 C>T) and one deletion mutation (c.307+?_513-?del exons 4, 5, 6). RT-PCR confirmed that IVS3+1 G>A generated an aberrant transcript with exon3 deletion. Immunohistochemical analysis demonstrated reduced nuclear parafibromin expression in tumours supporting the pathogenic effects of these mutations.


CONCLUSIONS
This study supplies information on mutations and phenotypes of HPT-JT/FIHP syndrome in Chinese. Screening for gross deletion and point mutations of the CDC73 gene is necessary in susceptible subjects.
Key laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Jing
J
Kong
Ou
O
Wang
Min
M
Nie
Jie
J
Shi
Yingying
Y
Hu
Yan
Y
Jiang
Mei
M
Li
Weibo
W
Xia
Xunwu
X
Meng
Xiaoping
X
Xing
D000236:Adenoma / Q000235:genetics*; D000328:Adult; D005260:Female; D005350:Fibroma / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics*; D049950:Hyperparathyroidism, Primary / Q000235:genetics*; D007150:Immunohistochemistry; D007573:Jaw Neoplasms / Q000235:genetics*; D008297:Male; D010282:Parathyroid Neoplasms / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
C454900:CDC73 protein, human; D025521:Tumor Suppressor Proteins