SASH1 S519N variant links skin hyperpigmentation and premature hair graying to dysfunction of melanocyte lineage

A better understanding of human melanocyte and melanocyte stem cell (McSC) biology is essential for treating melanocyte-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate the SASH1 function in melanocyte lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical exams, human cell assays, yeast two-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. We identified SASH1 as a novel regulator in McSC maintenance and discovered that TNKS2 is crucial for SASH1’s role in vitro. Additionally, the S519N variant is located in one of multiple tankyrase binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder showcases accelerated aging in human McSC, linking both gain and loss of pigmentation to McSC dysfunction in the same individuals. The findings offer new insights into the roles of SASH1 and TNKS2 in McSC maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with skin disorders should include an assessment and history of hair pigmentation loss.