MLPH – Griscelli Syndrome Type 3

MLPH encodes melanophilin, a critical linker of RAB27A and myosin Va that anchors mature melanosomes to peripheral actin filaments in melanocytes. Biallelic loss-of-function variants in MLPH cause Griscelli syndrome type 3 (GS3), characterized by hypopigmentation of skin and hair without immunological or neurological involvement. GS3 is inherited in an autosomal recessive manner and displays consistent melanosome aggregation in patient melanocytes.

Clinical validity of the MLPH–GS3 association is supported by multiple unrelated families and concordant functional data. A total of nine GS3 probands harbor pathogenic homozygous MLPH variants across five unrelated pedigrees: one Chinese patient with c.73G>C (p.Asp25His) (PMID:35602484), one Indian girl with pigment dilution (PMID:33235850), and seven individuals in three Arab pedigrees sharing c.103C>T (p.Arg35Trp) and c.104G>A (p.Arg35Gln) variants (PMID:21883982).

Genetic evidence under autosomal recessive inheritance includes homozygous missense alleles in conserved Slp homology domains segregating with hypopigmentation. The novel c.73G>C (p.Asp25His) variant resides in the Slp homology domain and was absent from controls, consistent with a likely pathogenic classification after in silico prediction and absence in population databases (PMID:35602484). Recurrent Arab pedigrees demonstrate segregation of c.103C>T (p.Arg35Trp) and c.104G>A (p.Arg35Gln) with GS3 phenotype in seven affected relatives (PMID:21883982).

Functional assays in patient-derived melanocytes show that MLPH(p.Asp25His) and MLPH(p.Arg35Trp) variants disrupt melanosome transport, causing perinuclear pigment aggregation and markedly reduced RAB27A binding despite normal protein levels (PMID:35602484; PMID:21883982). Co-immunoprecipitation confirmed loss of interaction between mutant MLPH and RAB27A, establishing a loss-of-function mechanism.

Animal and cellular models further corroborate MLPH haploinsufficiency in melanosome trafficking. Quail Mlph knockout and ZnF motif mutant lines exhibit diluted feather pigmentation with impaired dendritogenesis, reversible upon wild-type MLPH rescue in vitro (PMID:38760591). Rabbit MLPH frameshift variants phenocopy coat color dilution and reduce transcript stability, supporting conserved pathogenic mechanisms across species (PMID:30142960).

No conflicting reports have been identified. Integration of genetic and functional data yields a Strong clinical validity classification, a Moderate tier of genetic evidence, and a Moderate tier of functional evidence. MLPH sequencing is recommended for diagnostic confirmation of GS3 in patients presenting with isolated hypopigmentation.

References

• The Journal of clinical investigation • 2003 • Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1). PMID:12897212
• Pigment cell & melanoma research • 2012 • Cellular and clinical report of new Griscelli syndrome type III cases. PMID:21883982
• Frontiers in medicine • 2022 • Identification of a Novel MLPH Missense Mutation in a Chinese Griscelli Syndrome 3 Patient. PMID:35602484
• Indian dermatology online journal • 2020 • Griscelli Syndrome Type 3 with Coexistent Universal Dyschromia-An Uncommon Association of a Rare Entity. PMID:33235850
• Communications biology • 2024 • Melanophilin regulates dendritogenesis in melanocytes for feather pigmentation. PMID:38760591
• Genes • 2018 • New Insights into the Melanophilin (MLPH) Gene Affecting Coat Color Dilution in Rabbits. PMID:30142960

Evidence Based Scoring (AI generated)