HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.
We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.
Carpten
J D
JD
Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Robbins
C M
CM
Villablanca
A
A
Forsberg
L
L
Presciuttini
S
S
Bailey-Wilson
J
J
Simonds
W F
WF
Gillanders
E M
EM
Kennedy
A M
AM
Chen
J D
JD
Agarwal
S K
SK
Sood
R
R
Jones
M P
MP
Moses
T Y
TY
Haven
C
C
Petillo
D
D
Leotlela
P D
PD
Harding
B
B
Cameron
D
D
Pannett
A A
AA
Höög
A
A
Heath
H
H
James-Newton
L A
LA
Robinson
B
B
Zarbo
R J
RJ
Cavaco
B M
BM
Wassif
W
W
Perrier
N D
ND
Rosen
I B
IB
Kristoffersson
U
U
Turnpenny
P D
PD
Farnebo
L-O
LO
Besser
G M
GM
Jackson
C E
CE
Morreau
H
H
Trent
J M
JM
Thakker
R V
RV
Marx
S J
SJ
Teh
B T
BT
Larsson
C
C
Hobbs
M R
MR
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D002878:Chromosomes, Human, Pair 1; D005091:Exons; D020224:Expressed Sequence Tags; D016147:Genes, Tumor Suppressor; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics*; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010282:Parathyroid Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D013577:Syndrome; D025521:Tumor Suppressor Proteins
C454900:CDC73 protein, human; D011506:Proteins; D025521:Tumor Suppressor Proteins