RAB27A – Griscelli syndrome

Griscelli syndrome type 2 is an autosomal recessive disorder caused by biallelic loss-of-function variants in RAB27A, a small GTPase that regulates melanosome transport and cytotoxic granule exocytosis (PMID:10835631). Affected individuals present with pigmentary dilution of the skin and hair, partial albinism, immunodeficiency, and hemophagocytic lymphohistiocytosis (HLH), often accompanied by hepatosplenomegaly and cytopenias.

Inheritance is autosomal recessive, with homozygous or compound heterozygous variants confirmed in multiple consanguineous families; segregation of pathogenic alleles has been documented in at least 16 probands (PMID:10835631) and additional kindreds (PMID:12058346). Case reports include an 11-year-old girl harboring c.53_54del (p.Ser18fs) (PMID:12522785) and twin infants with c.514_518del (p.Gln172fs) presenting with HLH and pancytopenia (PMID:12648328).

The variant spectrum exceeds two dozen alleles, including frameshift, nonsense, splice-site, and missense changes. Founder and recurrent deletions have been identified, notably a 67.5-kb deletion eliminating RAB27A mRNA in an Arab pedigree (PMID:12058346).

Functional studies demonstrate that missense mutations such as p.Trp73Gly and p.Ala152Pro impair GTP binding and disrupt interactions with melanophilin/myosin-Va, abrogating melanosome transport in melanocytes (PMID:12531900). Cytotoxic lymphocyte assays reveal defective degranulation in patient cells, which is restored by retroviral RAB27A transfer (PMID:15163896).

Mechanistically, RAB27A deficiency leads to failure of lytic granule docking and exocytosis in NK and CD8+ T cells, precipitating HLH, while melanosome mislocalization underlies pigmentary changes. Animal and cellular models corroborate loss-of-function as the pathogenic mechanism, with gene therapy–mediated rescue offering a potential intervention.

Early molecular diagnosis of RAB27A variants facilitates timely HLH‐directed chemotherapy and hematopoietic stem cell transplantation, which remain the only curative options. Key take-home: biallelic RAB27A LoF unequivocally causes Griscelli syndrome type 2 with high clinical penetrance and well-characterized functional impact.

References

• Nature genetics • 2000 • Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. PMID:10835631
• American journal of human genetics • 2002 • Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A. PMID:12058346
• American journal of medical genetics. Part A • 2003 • Griscelli syndrome without hemophagocytosis in an eleven-year-old girl: expanding the phenotypic spectrum of Rab27A mutations in humans. PMID:12522785
• The Journal of biological chemistry • 2003 • Characterization of the molecular defects in Rab27a, caused by RAB27A missense mutations found in patients with Griscelli syndrome. PMID:12531900
• Journal of clinical immunology • 2004 • Griscelli syndrome: characterization of a new mutation and rescue of T-cytotoxic activity by retroviral transfer of RAB27A gene. PMID:15163896
• Annals of tropical paediatrics • 2003 • A rare syndrome in the differential diagnosis of hepatosplenomegaly and pancytopenia: report of identical twins with Griscelli disease. PMID:12648328

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