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Published on: December 19, 2019
Steroidogenic Factor-1 Lineage Origin of Skin Lesions in Carney Complex Syndrome
Isabelle Sahut-Barnola1, Anne-Marie Lefrançois-Martinez1, Damien Dufour1
1Institut Genetics, Reproduction & Development (iGReD), CNRS, Inserm, University of Clermont-Auvergne, France.
Abstract:
Carney complex is a rare familial multineoplastic syndrome predisposing to endocrine and nonendocrine tumors due to inactivating mutations of PRKAR1A, leading to perturbations of the cAMP‒protein kinase A signaling pathway. Skin lesions are the most common manifestation of Carney complex, including lentigines, blue nevi, and cutaneous myxomas in unusual locations such as oral and genital mucosa. Unlike endocrine disorders, the pathogenesis of skin lesions remains unexplained. In this study, we show that embryonic invalidation of the Prkar1a gene in steroidogenic factor-1‒expressing cells leads to the development of familial skin pigmentation alterations, reminiscent of those in patients with Carney complex. Immunohistological and molecular analyses, coupled with genetic monitoring of recombinant cell lineages in mouse skin, suggest that familial lentiginosis and myxomas occur in skin areas specifically enriched in dermal melanocytes. In lentigines- and blue nevi‒prone areas from mutant mice and patients, Prkar1a/PRKAR1A invalidation occurs in a subset of dermal fibroblasts capable of inducing, under the influence of protein kinase A signaling, the production of promelanogenic EDN3 and hepatocyte GF signals. Our model strongly suggests that the origin of the typical Carney complex cutaneous lesions is the result of noncell-autonomous promelanogenic activity of a dermal fibroblast population sharing a community of origin with steroidogenic factor-1 lineage.
Insights
Carney complex skin lesions arise from fibroblast dysfunction, not melanocyte issues. Inactivating PRKAR1A in specific fibroblasts triggers abnormal skin pigmentation, explaining lentigines and myxomas in this syndrome.
Area of Science:
- Genetics and Molecular Biology
- Dermatology
- Endocrinology
Background:
- Carney complex is a rare genetic disorder characterized by multiple tumors, linked to PRKAR1A gene mutations affecting cAMP-protein kinase A signaling.
- Skin manifestations, including lentigines, blue nevi, and myxomas, are common in Carney complex, but their underlying cause is poorly understood.
- While endocrine aspects are linked to PRKAR1A mutations, the pathogenesis of cutaneous lesions remains unclear.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms driving the characteristic skin lesions in Carney complex.
- To determine if genetic alterations in skin cells contribute to the development of lentigines and myxomas.
- To elucidate the role of the cAMP-protein kinase A pathway in the pathogenesis of Carney complex-associated skin manifestations.
Main Methods:
- Utilizing a mouse model with embryonic inactivation of the Prkar1a gene in steroidogenic factor-1 expressing cells.
- Performing immunohistological and molecular analyses on skin tissues from mutant mice and Carney complex patients.
- Employing genetic monitoring of recombinant cell lineages within mouse skin to trace cellular origins and interactions.
Main Results:
- Embryonic inactivation of Prkar1a in specific cells recapitulated skin pigmentation alterations similar to Carney complex.
- Familial lentiginosis and myxomas were observed in skin regions rich in dermal melanocytes.
- PRKAR1A inactivation in a subset of dermal fibroblasts, not melanocytes, induced promelanogenic signals (EDN3, HGF) via protein kinase A signaling.
Conclusions:
- The study identifies a novel mechanism for Carney complex skin lesion development, originating from dermal fibroblasts.
- Non-cell-autonomous signaling from affected fibroblasts drives abnormal melanocyte activity and pigment production.
- This research provides a new model suggesting that fibroblast dysfunction is the primary driver of Carney complex cutaneous manifestations.
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