RAB27A – Hemophagocytic Syndrome

Rab27a, encoded by RAB27A (HGNC:9766), is a small GTPase critical for cytotoxic granule exocytosis in natural killer (NK) cells and cytotoxic T lymphocytes. Loss-of-function variants in RAB27A cause Griscelli syndrome type 2 (GS2) and predispose to hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory disorder collectively referred to as hemophagocytic syndrome (MONDO:0015540).

GS2 follows an autosomal recessive inheritance pattern with biallelic pathogenic variants. In a cohort of 15 GS2 patients, 11 developed HLH (PMID:38187365). A novel homozygous RAB27A c.551G>A (p.Arg184Gln) variant was identified in a 35-year-old male presenting with recurrent fever and meeting HLH criteria (PMID:35870028). Targeted sequencing in 1892 patients with suspected HLH revealed pathogenic RAB27A variants in multiple cases, contributing to ∼10.4% of genetic diagnoses in this cohort (PMID:32542393).

The spectrum of RAB27A alleles includes missense, nonsense, splice-site, small indels, and a recurrent 38 kb exon 2–5 tandem duplication found in Saudi families (PMID:28585352). The c.551G>A (p.Arg184Gln) change selectively impairs lymphocyte exocytosis despite rescuing melanosome transport in melanocytes.

Functional studies demonstrate that RAB27A missense mutations disrupt effector interactions essential for cytotoxic granule release. The p.Arg184Gln variant shows reduced binding to SLP2A and increased affinity for MUNC13-4, failing to restore CD8+ T cell exocytosis (PMID:35870028). Other mutants (e.g., p.Leu130Pro, p.Trp73Gly) abrogate GTP binding or melanophilin interaction, confirming Rab27a’s dual role in pigmentation and immune function (PMID:12531900; PMID:12446441). Retroviral transfer of wild-type RAB27A rescues cytotoxic activity in patient T cells (PMID:15163896).

No studies have refuted the RAB27A–HLH association. A heterozygous p.Ala87Pro allele exerts a partial dominant-negative effect, illustrating that monoallelic variants can modulate onset but do not negate the recessive mechanism (PMID:26880764).

Integration of genetic and experimental data establishes a definitive gene–disease relationship: biallelic RAB27A variants abolish cytotoxic granule exocytosis, leading to HLH. Early genetic testing for RAB27A mutations informs prognosis and guides timely hematopoietic stem cell transplantation.

Key take-home: RAB27A variants cause autosomal recessive hemophagocytic syndrome through impaired lymphocyte degranulation; genetic diagnosis is essential for life-saving intervention.

References

• Journal of Clinical Immunology • 2022 • Novel RAB27A Variant Associated with Late-Onset Hemophagocytic Lymphohistiocytosis Alters Effector Protein Binding. [PMID:35870028]
• American Journal of Clinical and Experimental Immunology • 2023 • Hemophagocytic lymphohistiocytosis in children with Griscelli syndrome type 2: genetics, laboratory findings and treatment. [PMID:38187365]
• Blood Advances • 2020 • Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic HLH disorders. [PMID:32542393]
• Human Mutation • 2017 • A RAB27A duplication in several cases of Griscelli syndrome type 2: An explanation for cases lacking a genetic diagnosis. [PMID:28585352]
• 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]
• Blood • 2003 • Biochemical and functional characterization of Rab27a mutations occurring in Griscelli syndrome patients. [PMID:12446441]
• 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]
• Journal of Immunology • 2016 • A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis. [PMID:26880764]

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