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. 2025 Jun 23;35(12):2826-2836.e5.
doi: 10.1016/j.cub.2025.04.055. Epub 2025 May 15.

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

Christopher B Kaelin  1 , Kelly A McGowan  1 , Joshaya C Trotman  2 , Donald C Koroma  2 , Victor A David  3 , Marilyn Menotti-Raymond  3 , Emily C Graff  4 , Anne Schmidt-Küntzel  5 , Elena Oancea  2 , Gregory S Barsh  6
Affiliations

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

Christopher B Kaelin et al. Curr Biol. .

Abstract

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 (PKAC); 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.

Keywords: X inactivation; calico; coat color genetics; domestic cat; mosaicism; orange; pigment-type switching; tortoiseshell.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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