Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism.
BACKGROUND
Familial isolated hyperparathyroidism (FIHP) is a hereditary disorder characterised by uni- or multiglandular parathyroid disease. A subset of families are likely to be genetic variants of other familial tumour syndromes in which PHPT is the main feature, for example multiple endocrine neoplasia type 1 (MEN 1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT).


OBJECTIVE
To investigate seven families diagnosed with FIHP, each with two to eight affected family members, to clarify the underlying genetic mechanism.


METHODS
The entire MEN1 gene was sequenced for germline mutations and, in addition, tumour specimens were analysed in comparative genomic hybridisation and loss of heterozygosity studies.


RESULTS
Two families exhibited MEN1 mutations, L112V and 1658delG, which were associated with loss of the wild-type 11q13 alleles in all tumours analysed. In the remaining five families, no MEN1 mutation was identified.


CONCLUSIONS
These results support the involvement of the MEN1 tumour suppressor gene in the pathogenesis of some of the FIHP kindreds. However, loss on chromosome 11 was seen in all tumours exhibiting somatic deletions, although in two families the tumour deletions involved 11q distal to MEN1. We conclude that the altered MEN1 gene function is of importance in the development of FIHP.
Villablanca
Andrea
A
Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden. Andrea.Villablanca@cmm.ki.se
Wassif
Wassif S
WS
Smith
Thomas
T
Höög
Anders
A
Vierimaa
Outi
O
Kassem
Moustapha
M
Dwight
Trisha
T
Forsberg
Lars
L
Du
Quan
Q
Learoyd
Diana
D
Jones
Keston
K
Stranks
Steve
S
Juhlin
Claes
C
Teh
Bin Tean
BT
Carling
Tobias
T
Robinson
Bruce
B
Larsson
Catharina
C
D000328:Adult; D000368:Aged; D002880:Chromosomes, Human, Pair 11; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D017422:Sequence Analysis, DNA