A Novel IVS2-1G>A mutation causes aberrant splicing of the HRPT2 gene in a family with hyperparathyroidism-jaw tumor syndrome.
HRPT2, the gene associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, was previously mapped to 1q24-q32. It was recently cloned, and several germline mutations were found to predispose to HPT-JT syndrome. We sequenced the complete HRPT2 coding sequence and splice-junctional regions in a Korean family with HPT-JT syndrome and identified a novel germline mutation, IVS2-1G>A in intron 2, that caused the autosomal dominant trait of HPT-JT syndrome in this family. RT-PCR and sequencing of the transcripts revealed that this splicing mutation generated alternative splicing errors leading to the formation of two different transcripts, one with exon 3 deleted, the other lacking the first 23 bp of exon 3 due to the use of an internal splice acceptor in exon 3. Translation of both transcripts results in premature termination. In addition, we detected two novel somatic mutations of HRPT2 in malignant parathyroid tumors from the affected individuals. One, 85delG, causes premature termination; the other, an 18 bp in-frame deletion of 13_30delCTTAGCGTCCTGCGACAG, suggests that this region may be important in the development of the parathyroid carcinomas in HPT-JT syndrome. These findings provide further evidence that mutation of HRPT2 is associated with the formation of parathyroid tumors in HPT-JT syndrome.
Moon
Sung-Dae
SD
Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul 137-701, Korea.
Park
Jae-Hyun
JH
Kim
Eun-Min
EM
Kim
Ju-Hee
JH
Han
Je-Ho
JH
Yoo
Soon-Jib
SJ
Yoon
Kun-Ho
KH
Kang
Moo-Il
MI
Lee
Kwang-Woo
KW
Son
Ho-Yong
HY
Kang
Sung-Koo
SK
Oh
Se-Jeong
SJ
Kim
Kyung-Mi
KM
Yoon
Sung-Joo Kim
SJ
Park
Jae-Gahb
JG
Kim
Il-Jin
IJ
Kang
Hio Chung
HC
Hong
Soon-Won
SW
Kim
Kyung-Rae
KR
Cha
Bong-Yun
BY
D000328:Adult; D017398:Alternative Splicing; D001483:Base Sequence; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D017931:DNA Primers; D005220:Fathers; D018095:Germ-Line Mutation; D006801:Humans; D006961:Hyperparathyroidism / Q000000981:diagnostic imaging / Q000235:genetics*; D007573:Jaw Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D011859:Radiography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D025521:Tumor Suppressor Proteins
C454900:CDC73 protein, human; D017931:DNA Primers; D011506:Proteins; D025521:Tumor Suppressor Proteins