Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding.

[oculocutaneous albinism]

Familial hemophagocytic lymphohistiocytosis (FHL ) is a rare and often fatal disorder characterized by defective cellular cytotoxicity and hyperinflammation , and the only cure known to date is hematopoietic stem cell transplantation . Mutations in RAB 27 A , LYST , and AP 3 B 1 give rise to FHL associated with oculocutaneous albinism , and patients with FHL are usually only screened for mutations in these genes when albinism is observed . A Â number of patients with FHL and normal pigmentation remain without a genetic diagnosis .We asked whether patients with FHL with immunodeficiency but with normal pigmentation might sometimes have mutations that affected cellular cytotoxicity without affecting pigmentation .We carried out mutation analysis of RAB 27 A , LYST , and AP 3 B 1 in patients with FHL with pigment dilution , as well as a cohort with no clinical evidence of pigment dilution but no mutations in the other known FHL-related genes (PRF 1 , STXBP 2 , and UNC 13 D ).We identify patients with Griscelli syndrome type 2 with biallelic mutations in RAB 27 A in the absence of albinism . All 6 patients carried mutations at amino acids R 141 , Y 159 , or Â S 163 of Rab 27 a that disrupt the interaction of Rab 27 a with Munc 13 -4 , without impairing the interaction between melanophilin and Rab 27 a .These studies highlight the need for RAB 27 A sequencing in patients with FHL with normal pigmentation and identify a critical binding site for Munc 13 -4 on Rab 27 a , revealing the molecular basis of this interaction .

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Diseases presenting "and patients with fhl are usually only screened for mutations in these genes when albinism is observed" symptom

oculocutaneous albinism

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