Inheritance, mode of inheritance, and candidate genes for primary hyperparathyroidism in Keeshonden.
BACKGROUND
Primary hyperparathyroidism (PHPT) is caused by inappropriate secretion of parathyroid hormone (PTH) by autonomously functioning neoplastic or hyperplastic parathyroid "chief" cells. Keeshonden are thought to be over-represented in studies on canine PHPT, but no proof of heritability or mode of inheritance has been published. The canine disease clinically resembles human familial isolated hyperparathyroidism (FIHP).


OBJECTIVE
Primary hyperparathyroidism in Keeshonden is genetically transmitted and is caused by a mutation in 1 of 4 genes implicated in human FIHP: MEN1, CASR, HRPT2, or RET.


METHODS
Pedigrees consisting of 1647 Keeshonden were created including 219 Keeshonden with known PHPT phenotypes (69 positive). DNA samples were obtained from 176 of the 219 Keeshonden (34 positive).


METHODS
Heritability and mode of inheritance were determined by segregation analysis. Canine homologs to the human genes were identified. Exons and surrounding intron regions were sequenced and scanned for sense-altering polymorphisms or polymorphisms that segregated with the disease. Messenger RNA from a parathyroid tumor of an affected Keeshond was analyzed for polymorphisms and splice alterations.


RESULTS
PHPT follows an autosomal dominant mode of inheritance in Keeshonden with possible age-dependent penetrance. No polymorphisms identified in the genes analyzed were associated with a change in predicted protein or in hypothesized splice sites.


CONCLUSIONS
PHPT is an autosomal dominant, genetically transmitted disease in Keeshonden. Once the mutation locus is identified, genetic testing should quickly decrease the incidence of PHPT in this breed. It is unlikely that mutations in MEN1, CASR, HRPT2, or RET cause PHPT in Keeshonden.
Goldstein
Richard E
RE
Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. rg225@cornell.edu
Atwater
Daniel Z
DZ
Cazolli
Dava M
DM
Goldstein
Orly
O
Wade
Claire M
CM
Lindblad-Toh
Kerstin
K
D000818:Animals; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D006961:Hyperparathyroidism / Q000235:genetics / Q000662:veterinary*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012313:RNA / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D011518:Proto-Oncogene Proteins; D044169:Receptors, Calcium-Sensing; D025521:Tumor Suppressor Proteins; D012313:RNA; D020794:Receptor Protein-Tyrosine Kinases