Mutation analysis of MEN1, HRPT2, CASR, CDKN1B, and AIP genes in primary hyperparathyroidism patients with features of genetic predisposition.
OBJECTIVE
Primary hyperparathyroidism (PHPT), a common endocrine condition, is usually caused by sporadically occurring parathyroid adenoma. A subset of patients carry germline mutations in genes such as MEN1 (multiple endocrine neoplasia type 1), HRPT2 (hyperparathyroidism 2), and CASR (calcium-sensing receptor) predisposing to syndromic forms of PHPT or familial isolated hyperparathyroidism (FIHP). Recently, germline mutations in two novel genes AIP (aryl hydrocarbon receptor-interacting protein) and CDKN1B (cyclin-dependent kinase inhibitor 1B) have been found to be associated with endocrine tumors. The purpose of this study was to evaluate the role of MEN1, HRPT2, CASR, AIP, and CDKN1B genes in PHPT patients with clinical features suggestive of genetic predisposition.


METHODS
Medical records of patients treated for PHPT from 1974 to 2001 at Oulu University Hospital were reviewed. Patients with multiglandular or recurrent/persistent disease, other MEN1- related manifestations, aged 40 yr or younger at onset or with a family history of PHPT/MEN1-related tumor were invited to the study. Twenty patients with previously diagnosed MEN1 were excluded. Participants were interviewed and blood samples obtained for biochemical screening and mutation analysis of MEN1, HRPT2, CASR, AIP, and CDKN1B.


RESULTS
Of the 56 invited patients, 29 took part in the study. One patient was found to carry the c. 1356_1367del12 MEN1 founder mutation. Mutations in other genes were not detected.


CONCLUSIONS
Apart from MEN1, mutations in other genes predisposing to PHPT seem to be rare or non-existing in Northern Finnish PHPT patients. No evidence was found for a role of AIP or CDKN1B in PHPT predisposition.
Vierimaa
O
O
Department of Clinical Genetics, Oulu University Hospital, PB 24, FIN-90029 Oys, Oulu, Finland. outi.vierimaa@oulu.fi
Villablanca
A
A
Alimov
A
A
Georgitsi
M
M
Raitila
A
A
Vahteristo
P
P
Larsson
C
C
Ruokonen
A
A
Eloranta
E
E
Ebeling
T M L
TM
Ignatius
J
J
Aaltonen
L A
LA
Leisti
J
J
Salmela
P I
PI
D000328:Adult; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000235:genetics* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics; D044169:Receptors, Calcium-Sensing / Q000737:chemistry / Q000235:genetics; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics; D055815:Young Adult
C095550:CASR protein, human; C454900:CDC73 protein, human; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D044169:Receptors, Calcium-Sensing; D025521:Tumor Suppressor Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA