Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.

TitleGermline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.
Publication TypeJournal Article
Year of Publication2015
AuthorsLodish, MB, Yuan, B, Levy, I, Braunstein, GD, Lyssikatos, C, Salpea, P, Szarek, E, Karageorgiadis, AS, Belyavskaya, E, Raygada, M, Faucz, FRueda, Izzat, L, Brain, C, Gardner, J, Quezado, M, J Carney, A, Lupski, JR, Stratakis, CA
JournalEur J Endocrinol
Date Published2015 06
KeywordsAdrenal Glands, Adrenalectomy, Adult, Child, Child, Preschool, Cushing Syndrome, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, DNA Copy Number Variations, Female, Gene Amplification, Humans, Hyperplasia, Male, Phenotype, Young Adult

OBJECTIVE: We have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype-phenotype correlation of their PRKACA amplification.

DESIGN: This study is a case series.

METHODS: Molecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS.

RESULTS: Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entire PRKACA gene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient, PRKACA triplication was associated with a more severe phenotype.

CONCLUSIONS: Constitutional chromosomal PRKACA gene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication. PRKACA amplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.

Alternate JournalEur J Endocrinol
PubMed ID25924874
PubMed Central IDPMC4428149
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
Z01 HD000642-10 / / Intramural NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States

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