Large deletions of the PRKAR1A gene in Carney complex
Anelia Horvath1, Ioannis Bossis, Christoforos Giatzakis
1Section on Endocrinology and Genetics and Pediatric Endocrinology Training Program, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
Purpose:
Since the identification of PRKAR1A mutations in Carney complex, substitutions and small insertions/deletions have been found in approximately 70% of the patients. To date, no germ-line PRKAR1A deletion and/or insertion exceeded a few base pairs (up to 15). Although a few families map to chromosome 2, it is possible that current sequencing techniques do not detect larger gene changes in PRKAR1A -- mutation-negative individuals with Carney complex.
Experimental Design:
To screen for gross alterations of the PRKAR1A gene, we applied Southern hybridization analysis on 36 unrelated Carney complex patients who did not have small intragenic mutations or large aberrations in PRKAR1A, including the probands from two kindreds mapping to chromosome 2.
Results:
We found large PRKAR1A deletions in the germ-line of two patients with Carney complex, both sporadic cases; no changes were identified in the remaining patients, including the two chromosome-2-mapping families. In the first patient, the deletion is expected to lead to decreased PRKAR1A mRNA levels but no other effects on the protein; the molecular phenotype is predicted to be PRKAR1A haploinsufficiency, consistent with the majority of PRKAR1A mutations causing Carney complex. In the second patient, the deletion led to in-frame elimination of exon 3 and the expression of a shorter protein, lacking the primary site for interaction with the catalytic protein kinase A subunit. In vitro transfection studies of the mutant PRKAR1A showed impaired ability to bind cyclic AMP and activation of the protein kinase A enzyme. The patient bearing this mutation had a more-severe-than-average Carney complex phenotype that included the relatively rare psammomatous melanotic schwannoma.
Conclusions:
Large PRKAR1A deletions may be responsible for Carney complex in patients that do not have PRKAR1A gene defects identifiable by sequencing. Preliminary data indicate that these patients may have a different phenotype especially if their defect results in an expressed, abnormal version of the PRKAR1A protein.
Insights
Large PRKAR1A deletions are newly identified as a cause of Carney complex in some patients. These deletions, missed by sequencing, may lead to distinct clinical features, particularly when they result in abnormal protein expression.
Area of Science:
- Genetics
- Molecular Biology
- Endocrinology
Background:
- Carney complex is a rare genetic disorder often linked to PRKAR1A mutations.
- Current genetic testing primarily identifies substitutions and small insertions/deletions in PRKAR1A, accounting for about 70% of cases.
- Larger PRKAR1A gene alterations may be missed by standard sequencing techniques in mutation-negative patients.
Purpose of the Study:
- To investigate the presence of gross alterations, specifically large deletions, in the PRKAR1A gene.
- To screen mutation-negative Carney complex patients for large PRKAR1A deletions using Southern hybridization.
Main Methods:
- Southern hybridization analysis was performed on 36 unrelated Carney complex patients.
- Patients included those without detectable small intragenic mutations or large aberrations in PRKAR1A, and probands from two families linked to chromosome 2.
Main Results:
- Large germ-line PRKAR1A deletions were identified in two sporadic Carney complex patients.
- One deletion resulted in PRKAR1A haploinsufficiency, while the other caused an in-frame deletion of exon 3, leading to a shorter, abnormal protein.
- The patient with the abnormal protein exhibited a more severe Carney complex phenotype, including psammomatous melanotic schwannoma.
Conclusions:
- Large PRKAR1A deletions represent a potential cause of Carney complex in patients with sequencing-undetectable defects.
- These deletions may be associated with distinct clinical phenotypes, especially when they lead to the expression of an abnormal PRKAR1A protein.
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