MYO5A – Griscelli syndrome type 1

Griscelli syndrome type 1 (GS1) is a rare autosomal recessive disorder caused by biallelic pathogenic variants in MYO5A and characterized by pigment dilution, neurologic impairment, motor disability and hypotonia (HP:0001252) in Griscelli syndrome type 1 (PMID:36651988). Patients present with general hypopigmentation of skin and hair, early-onset developmental delay, muscle weakness and vision abnormalities.

Genetic studies have identified at least 11 probands (including two affected siblings) harboring homozygous or compound heterozygous truncating MYO5A variants, consistent with autosomal recessive inheritance (PMID:36651988). In a consanguineous Iranian family, the novel homozygous frameshift variant co-segregated with disease in two affected siblings and was absent from unaffected relatives (2 segregations) (PMID:36651988). All reported pathogenic variants in GS1 are predicted loss-of-function, supporting haploinsufficiency as the mechanism.

The key recurrent variant c.1633_1634del (p.Asn545GlnfsTer10) leads to a premature stop codon upstream of the cargo-binding domain and was classified as pathogenic per ACMG guidelines (PMID:36651988). This frameshift alters the motor domain and abolishes MyoVa-driven melanosome trafficking.

Functional assays in melanocytes and model organisms demonstrate that disruption of the RAB27A–MLPH–MYO5A tripartite complex impairs melanosome transport along actin filaments, recapitulating the hypopigmentation phenotype observed in GS1 (PMID:19243575). Yeast and mammalian cell studies confirm that MyoVa deficiency abrogates peripheral melanosome distribution, supporting loss-of-function as the pathogenic mechanism.

No studies have refuted the MYO5A–GS1 association. Subtypes GS2 and GS3 are caused by RAB27A and MLPH mutations, but only MYO5A variants are tied to GS1.

In summary, consanguineous and unrelated case series establish a definitive autosomal recessive link between truncating MYO5A variants and GS1, with concordant functional data on melanosome transport. Key take-home: MYO5A sequencing for early diagnosis and carrier screening is critical in families with hypopigmentation and neuromuscular involvement.

References

• Molecular genetics and genomics • 2023 • Griscelli syndrome type 1: a novel pathogenic variant, and review of literature. PMID:36651988
• Pigment cell & melanoma research • 2009 • Griscelli syndrome: a model system to study vesicular trafficking. PMID:19243575

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