MLPH gene

The MLPH gene (MLPH stands for melanophilin) is a protein-coding gene located on chromosome 2q37.3. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. Activities of the gene include actin binding and myosin binding. An important paralog of this gene is MYRIP.

The MLPH gene encodes a member of the exophilin subfamily of Rab effector proteins. The protein forms a ternary complex with the small Ras-related GTPase Rab27A in its GTP-bound form and the motor protein MYO5A. A similar protein complex in the mouse has the function of binding melanosomes to the actin cytoskeleton in melanocytes and is required for visible pigmentation in hair and skin.

The Mlph protein melanophilin encoded by this gene plays a crucial role in the regulation of skin pigmentation through the melanosome transport process. The expression of Mlph is regulated by the glucocorticoid receptor (GR). Alteration of GR activity by a specific GR agonist or antagonist only regulated the expression of Mlph among the three major melanosome transport proteins.

Melanosomes are transported by kinesin, dynein and myosin motors. Therefore, melanosome transport is ideally suited to study the functional relationship between the microtubule and actin-based transport systems. In mammalian melanocytes, the Rab27a/melanophilin/myosin-Va complex is known to mediate actin-based transport in vivo. Melanophilin, in particular its C-terminal actin-binding domain (ABD), plays a major role in the pathways that regulate the overall directionality of melanosomes on the actin/microtubule networks. Dephosphorylated melanophilin binds preferentially to microtubules even in the presence of actin, whereas phosphorylated melanophilin associates with actin. In the simultaneous presence of actin and microtubules, the phosphorylation state of melanophilin led to the activation of the Rab27a/melanophilin/myosin-Va transport complex (Oberhofer A et al. 2017).

A mutation in this gene leads to Griscelli syndrome type 3, which is characterized by a silver-grey hair color and abnormal pigment distribution in the hair shaft, among other things.

1. Alves CP et al. (2017) MYO5A Gene Is a Target of MITF in Melanocytes. J Invest Dermatol 137:985-989.
2. Guo D et al. (2020) RAB27A/Melanophilin Blocker Inhibits Melanoma Cell Motility and Invasion. J Invest Dermatol 140:1470-1473.e3.
3. Khorram E et al. (2023) Griscelli syndrome type 1: a novel pathogenic variant, and review of literature. Mol Genet Genomics 298:485-493.
4. Mohammadzadeh Shanehsaz S et al. (2015) Elejalde syndrome (ES). Dermatol Online J 21:13030/qt96833983.
5. Oberhofer A et al.(2017) Myosin Va's adaptor protein melanophilin enforces track selection on the microtubule and actin networks in vitro. Proc Natl Acad Sci U S A 114:E4714-E4723.