Molecular and genetic characterization of sex-linked orange coat color in the domestic cat

The Sex-linked orange mutation in domestic cats causes variegated patches of reddish/yellow hair and is a defining signature of random X inactivation in female tortoiseshell and calico cats. Unlike the situation for most coat color genes, there is no apparent homolog for Sex-linked orange in other mammals. We show that Sex-linked orange is caused by a 5-kb deletion that leads to ectopic and melanocyte-specific expression of the Rho GTPase Activating Protein 36 (Arhgap36) gene. Single-cell RNA sequencing (RNA-seq) studies from fetal cat skin reveal that red/yellow hair color is caused by reduced expression of melanogenic genes that are normally activated by the melanocortin 1 receptor (Mc1r)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, but Mc1r and its ability to stimulate cAMP accumulation is intact. Instead, we show that expression of Arhgap36 in melanocytes leads to reduced levels of the PKA catalytic subunit (PKA(C)); thus, Sex-linked orange is genetically and biochemically downstream of Mc1r. Our findings resolve a longstanding comparative genetic puzzle, provide in vivo evidence for the ability of Arhgap36 to inhibit PKA, and reveal a molecular explanation for a charismatic color pattern with a rich genetic history.

Authors: C. B. Kaelin, K. A. McGowan, J. C. Trotman, D. C. Koroma, V. A. David, M. Menotti-Raymond, E. C. Graff, A. Schmidt-Küntzel, E. Oancea and G. S. Barsh Title: Molecular and genetic characterization of sex-linked orange coat color in the domestic cat Full source: Curr Biol, 2025,Vol 35, Iss 12, pp 2826-2836 e5
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Abstract	Source
The Sex-linked orange mutation in domestic cats causes variegated patches of reddish/yellow hair and is a defining signature of random X inactivation in female tortoiseshell and calico cats. Unlike the situation for most coat color genes, there is no apparent homolog for Sex-linked orange in other mammals. We show that Sex-linked orange is caused by a 5-kb deletion that leads to ectopic and melanocyte-specific expression of the Rho GTPase Activating Protein 36 (Arhgap36) gene. Single-cell RNA sequencing (RNA-seq) studies from fetal cat skin reveal that red/yellow hair color is caused by reduced expression of melanogenic genes that are normally activated by the melanocortin 1 receptor (Mc1r)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, but Mc1r and its ability to stimulate cAMP accumulation is intact. Instead, we show that expression of Arhgap36 in melanocytes leads to reduced levels of the PKA catalytic subunit (PKA(C)); thus, Sex-linked orange is genetically and biochemically downstream of Mc1r. Our findings resolve a longstanding comparative genetic puzzle, provide in vivo evidence for the ability of Arhgap36 to inhibit PKA, and reveal a molecular explanation for a charismatic color pattern with a rich genetic history.