Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients.
OBJECTIVE
Aberrant cAMP signaling is involved in the pathogenesis of somatotropinomas. The aim of the study was to screen acromegalic patients for the presence of variants of phosphodiesterase type 11A (PDE11A) gene, which have been recently identified in adrenocortical and testicular tumors.


METHODS
We sequenced the PDE11A gene-coding region in 78 acromegalic patients and 110 controls. Immunohistochemistry for PDE11A was performed in a subgroup of adenomas and normal pituitary samples.


RESULTS
We found 15 nonsynonymous germline substitutions in 13 acromegalic patients (17%), i.e. 14 missense variants (Y727C in six, R804H in one, R867G in four, and M878V in three) and one truncating mutation (FS41X), with a prevalence only slightly higher than that observed in controls (14%). Immunohistochemistry revealed PDE11A expression higher in somatotropinomas than in normal somatotrophs, without significant difference between tumors with or without PDE11A variants, with the exception of two tumors (one with loss of heterozygosity (LOH) at the PDE11A locus and one with FS41X mutation) showing markedly reduced PDE11A staining. No significant differences in hormonal and clinical parameters between patients with or without PDE11A variants were observed, although patients with PDE11A changes showed a tendency to have a more aggressive tumor compared with patients with wild-type sequence (extrasellar extension in 69 vs 45%).


CONCLUSIONS
This study first demonstrated the presence of PDE11A variants in a subset of acromegalic patients, which was only slightly more frequent than in controls. The normal expression of the enzyme in the majority of tumor tissues together with the lack of significant clinical phenotype suggests that these variants might only marginally contribute to the development of somatotropinomas.
Peverelli
E
E
Endocrinology and Diabetology Unit, Department of Medical Sciences, University of Milan, Padiglione Granelli, Fondazione Ospedale Maggiore IRCCS, Via F Sforza, 35, 20122 Milan, Italy.
Ermetici
F
F
Filopanti
M
M
Elli
F M
FM
Ronchi
C L
CL
Mantovani
G
G
Ferrero
S
S
Bosari
S
S
Beck-Peccoz
P
P
Lania
A
A
Spada
A
A
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000172:Acromegaly / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D000236:Adenoma / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D000328:Adult; D001483:Base Sequence; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D016133:Polymerase Chain Reaction; D012044:Regression Analysis
D004273:DNA, Neoplasm; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human