Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility.
Germline mutations in the von Hippel-Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma (RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-α subunits (and hence expression of the HIF-α transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (n=82) and inherited RCC (n=64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC.
Astuti
Dewi
D
Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham B15 2TT, UK.
Ricketts
Christopher J
CJ
Chowdhury
Rasheduzzaman
R
McDonough
Michael A
MA
Gentle
Dean
D
Kirby
Gail
G
Schlisio
Susanne
S
Kenchappa
Rajappa S
RS
Carter
Bruce D
BD
Kaelin
William G
WG
Ratcliffe
Peter J
PJ
Schofield
Christopher J
CJ
Latif
Farida
F
Maher
Eamonn R
ER
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured; D055815:Young Adult
D011393:Procollagen-Proline Dioxygenase