Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Griscelli syndrome type 2 (GS2; MONDO:0011872) is a rare autosomal recessive disorder caused by biallelic mutations in RAB27A (Gene Symbol). Clinically, GS2 presents with partial albinism, immunodeficiency, and life-threatening hemophagocytic lymphohistiocytosis (HLH) due to defective cytotoxic granule exocytosis. RAB27A encodes a small GTPase that binds tissue-specific effectors to regulate melanosome transport in melanocytes and lytic granule secretion in cytotoxic lymphocytes.
Genetic studies have identified 149 patients with GS2 harboring homozygous or compound heterozygous RAB27A variants across multiple populations ([PMID:39607447]). Segregation of pathogenic alleles has been confirmed in 7 unrelated families and 2 sibships with affected siblings and heterozygous carrier parents, consistent with autosomal recessive inheritance ([PMID:18350256]; [PMID:24678334]). Over 100 unique variants have been reported, including 56 protein-truncating variants (nonsense, frameshift, large deletions) and numerous missense and splice-site changes, supporting a loss-of-function mechanism ([PMID:39607447]).
A recurrent founder allele, c.244C>T (p.Arg82Cys), has been described in Qatari families (12 cases) exhibiting marked phenotypic heterogeneity ranging from asymptomatic hypopigmentation to early-onset HLH ([PMID:32856792]). Other hot-spot deletions such as c.514_518del (p.Gln172_Ser201del) have been identified in Iranian cohorts and Persian families ([PMID:28585352]). Carrier frequency and prevalence estimates remain limited but over 160 cases have been documented worldwide ([PMID:37791210]).
Functional assays demonstrate that disease-causing RAB27A missense variants impair GTP binding and disruption of effector interactions. Rab27A(K22R) and Rab27A(I44T) mutants fail to bind melanophilin/Slac2-a and other effectors with differential biochemical consequences in melanocytes ([PMID:20370853]). Biochemical and cell-based studies of W73G, L130P, and A152P mutants reveal abrogated GTPase activity, defective complex formation with melanophilin/myosin-Va, and dominant negative effects on melanosome transport ([PMID:12446441]; [PMID:12531900]).
In immune cells, RAB27A deficiency leads to impaired lytic granule docking and release. Patient CD8+ T cells and NK cells exhibit defective degranulation, reversible by retroviral RAB27A gene transfer in vitro ([PMID:15163896]). The Munc13-4–Rab27A complex is essential for secretory lysosome tethering at the plasma membrane in cytotoxic lymphocytes; mutations disrupting this interaction underlie HLH predisposition ([PMID:15548590]).
Overall, the evidence meets Definitive ClinGen criteria: over 149 probands, segregation in multiple families, and extensive concordant functional data. The genetic evidence is Strong—biallelic loss-of-function mutations in diverse populations. The functional evidence is Strong—multiple orthogonal assays and rescue experiments confirm pathogenic mechanisms. Early molecular diagnosis of RAB27A mutations enables prompt HLH management and curative hematopoietic stem cell transplantation.
Key Take-home: RAB27A mutation testing is critical for confirming GS2, guiding life-saving therapy and genetic counseling.
Gene–Disease AssociationDefinitive149 probands, segregation in multiple families, concordant functional data Genetic EvidenceStrong149 patients with biallelic RAB27A variants across multiple families; reached genetic evidence cap Functional EvidenceStrongDiverse biochemical assays demonstrating loss of GTP binding, effector interaction defects, and rescue by gene transfer |