Functional characterization of Griscelli syndrome type 2 sine albinism in Japanese patients

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Abstract
Griscelli syndrome type 2 (GS2), caused by biallelic RAB27A variants, is classically associated with hypopigmentation and life-threatening hemophagocytic lymphohistiocytosis (HLH). However, a few patients exhibit normal pigmentation, termed GS2 sine albinism. We identified two unrelated Japanese patients with this presentation caused by compound heterozygous RAB27A variants, representing the first functionally characterized cases among Japanese patients. Functional studies were performed using RAB27A-null cell systems to evaluate the two allele pairs: p.Trp73Arg/p.Val143Ala (patient 1) and p.Ser106PhefsTer18/p.Ser115Arg (patient 2). The truncating allele p.Ser106PhefsTer18 and the missense allele p.Trp73Arg failed to restore peripheral melanosome distribution and lost binding to both melanophilin (MLPH) and MUNC13-4. In contrast, p.Val143Ala and p.Ser115Arg preserved MLPH interaction but showed reduced binding to MUNC13-4. These findings demonstrate that RAB27A variants can dissociate melanosome transport from immune effector function in an allele-dependent manner. Importantly, the absence of hypopigmentation does not exclude GS2. Combined genetic and functional analyses are essential for precise variant interpretation and for guiding timely curative intervention in GS2.
Funding Information
  • Ministry of Education, Culture, Sports, Science and Technology (24K22081)
  • Ministry of Education, Culture, Sports, Science and Technology (25K02267)
  • Ministry of Education, Culture, Sports, Science and Technology (25K02618)
  • Ministry of Education, Culture, Sports, Science and Technology (26K10721)

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