Evaluating the Role of MC1R Variants in Cutaneous and Ocular Phenotypes: A Candidate TYR-MC1R Genetic Interaction in Oculocutaneous Disorders.
11 affiliations
- 1Department of Molecular Medicine, University of Padova, 35121 Padova, Italy.
- 2Clinical Genetics Unit, Department of Integrated Diagnostic Services, University Hospital of Padova, 35128 Padova, Italy.
- 3Center for Retinitis Pigmentosa of Veneto Region (ERN-EYE Network), Camposampiero Hospital, Azienda ULSS 6 Euganea, 35121 Padova, Italy.
- 4Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy.
- 5Medical Genetics Unit, Treviso Hospital, 31100 Treviso, Italy.
- 6Department of Women's and Children's Health, University of Padova, 35121 Padova, Italy.
- 7Fondazione Banca degli Occhi del Veneto ETS, 30174 Venice, Italy.
- 8King Khaled Eye Specialist Hospital, Riyadh 12211, Saudi Arabia.
- 9Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
- 10Robert Hollman Foundation, 35121 Padova, Italy.
- 11Fondazione Banca dei Tessuti del Veneto ETS, 31100 Treviso, Italy.
Abstract
Background: The melanocortin-1 receptor (MC1R) gene is a major determinant of skin and hair color. Although several MC1R variants increase the risk of skin tumors regardless of pigmentation, their role as genetic modifiers in ocular diseases remains poorly understood. Methods: Here, we analyzed a cohort of 48 Caucasian individuals using a custom next-generation sequencing (NGS) panel targeted for oculocutaneous disorders. Results:MC1R variants were identified in two probands selected from this cohort, exhibiting distinctly divergent pathological phenotypes. The first patient, an adult male with a pheomelanin-related trait and a history of early-onset skin cancer without ocular abnormalities, carried compound heterozygous MC1R variants: the novel frameshift c.537dupC (p.Ile180Hisfs*59) and the known c.880G>C (p.Asp294His). Conversely, the second patient, a young boy with severe vision-threatening features-including congenital nystagmus, foveal hypoplasia, and an atypical visual-pathway misrouting pattern-carried a candidate digenic genotype combining the same MC1R c.880G>C variant with the albinism-related c.1209G>T (p.Arg403Ser) variant in the tyrosinase (TYR) gene. Conclusions: While MC1R variants have previously been proposed as phenotypic modifiers in albinism, primarily in combination with the oculocutaneous type II melanosomal transmembrane protein (OCA2) encoding gene, our findings support a potential role for MC1R as a candidate modifier interacting with TYR in neuroretinal development. Although functional validation is required to establish causality, incorporating MC1R screening in patients with unresolved foveal hypoplasia may help clarify complex oligogenic mechanisms and optimize phenotypic classification.
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BibTeX
@article{iorio2026evaluating,
title = {{Evaluating the Role of MC1R Variants in Cutaneous and Ocular Phenotypes: A Candidate TYR-MC1R Genetic Interaction in Oculocutaneous Disorders.}},
author = {Enzo Di Iorio and Francesco Parmeggiani and Antonella De Nardi and Francesco Prevedello and Rebecca Affuso and Anna Demarinis and Andrea Gazzin and Chiara Rigon and Vanessa Barbaro and Katia De Nadai and Antonio Cartabellotta and Ginevra Giovanna Adamo and Marco Mura and Agnese Suppiej and Giorgio Palù and Leonardo Salviati and Marco Tavolato},
journal = {Genes},
year = {2026},
month = oct,
doi = {10.3390/genes17101289},
url = {https://europepmc.org/article/MED/42938405},
note = {CC BY},
}
RIS
TY - JOUR
TI - Evaluating the Role of MC1R Variants in Cutaneous and Ocular Phenotypes: A Candidate TYR-MC1R Genetic Interaction in Oculocutaneous Disorders.
AU - Enzo Di Iorio
AU - Francesco Parmeggiani
AU - Antonella De Nardi
AU - Francesco Prevedello
AU - Rebecca Affuso
AU - Anna Demarinis
AU - Andrea Gazzin
AU - Chiara Rigon
AU - Vanessa Barbaro
AU - Katia De Nadai
AU - Antonio Cartabellotta
AU - Ginevra Giovanna Adamo
AU - Marco Mura
AU - Agnese Suppiej
AU - Giorgio Palù
AU - Leonardo Salviati
AU - Marco Tavolato
PY - 2026
DA - 2026/10/15
JO - Genes
DO - 10.3390/genes17101289
UR - https://europepmc.org/article/MED/42938405
AB - Background: The melanocortin-1 receptor (MC1R) gene is a major determinant of skin and hair color. Although several MC1R variants increase the risk of skin tumors regardless of pigmentation, their role as genetic modifiers in ocular diseases remains poorly understood. Methods: Here, we analyzed a cohort of 48 Caucasian individuals using a custom next-generation sequencing (NGS) panel targeted for oculocutaneous disorders. Results:MC1R variants were identified in two probands selected from this cohort, exhibiting distinctly divergent pathological phenotypes. The first patient, an adult male with a pheomelanin-related trait and a history of early-onset skin cancer without ocular abnormalities, carried compound heterozygous MC1R variants: the novel frameshift c.537dupC (p.Ile180Hisfs*59) and the known c.880G>C (p.Asp294His). Conversely, the second patient, a young boy with severe vision-threatening features-including congenital nystagmus, foveal hypoplasia, and an atypical visual-pathway misrouting pattern-carried a candidate digenic genotype combining the same MC1R c.880G>C variant with the albinism-related c.1209G>T (p.Arg403Ser) variant in the tyrosinase (TYR) gene. Conclusions: While MC1R variants have previously been proposed as phenotypic modifiers in albinism, primarily in combination with the oculocutaneous type II melanosomal transmembrane protein (OCA2) encoding gene, our findings support a potential role for MC1R as a candidate modifier interacting with TYR in neuroretinal development. Although functional validation is required to establish causality, incorporating MC1R screening in patients with unresolved foveal hypoplasia may help clarify complex oligogenic mechanisms and optimize phenotypic classification.
SN - 2073-4425
ER -