Albinism: from genetics to cell biology and physiopathology

Abstract

Albinism classically encompasses several forms: oculocutaneous (OCA), ocular (OA1 and Foveal hypoplasia optic nerve decussation defect anterior segment dysgenesis syndrome [FHONDA]), and syndromic (Hermansky-Pudlak syndrome [HPS], Chediak-Higashi syndrome [CHS]), with all being autosomal recessive except X-linked recessive OA1. Twenty-one genes are identified to date, with OCA1 being most common in Europeans or patients of European descent and OCA2 in Sub-Saharan Africans. Their sequencing provides a diagnostic rate of ∼70 %, though unresolved cases may arise from variants in poorly explored non-coding regions, undetected genes, or differential diagnoses. The cellular and molecular mechanisms underlying non-syndromic forms of albinism affect the ability of pigment cells to synthesize melanin pigments in melanosomes, mainly through defects in melanogenic enzymes, or in ion channels or transporters affecting melanosome pH regulation. In contrast, syndromic forms of albinism (e.g., HPS subtypes) are membrane trafficking disorders caused by mutations in multi-subunit protein complexes (e.g., BLOC1, BLOC2, BLOC3, or AP-3) targeting the formations and functions of certain lysosome-related organelles (LROs), of which the melanosome is a prototypical member. Integrating clinical, genetic and fundamental research is essential for a comprehensive understanding of albinism, from patient manifestations to identifying molecular targets and elucidating their cell and tissue-specific functions, ultimately paving the way for improved diagnostics and therapeutic strategies.

Keywords: Albinism; Genetic disease; Hermansky-Pudlak syndrome; Intracellular trafficking; Melanin; Melanosome; Pigmentation.