This report describes mucolipidosis IV (ML4), which is inherited as an autosomal recessive and is caused by defects in the Mucolipin 1 (MCOLN1) gene. The MCOLN1 protein is cation channel found in the membranes of lysosomes and endosomes and appears to play a role in transport along the lysosomal pathway and/or late steps of endocytosis. There is a single Drosophila ortholog of MCOLN1, Dmel\Trpml, for which classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Trpml is also orthologous to two additional human genes, MCOLN2 and MCOLN3.
Several UAS constructs of the wild-type human Hsap\MCOLN1 gene have been introduced into flies. Partial heterologous rescue (functional complementation) has been demonstrated for the pupal-lethal phenotype of amorphic Dmel\Trpml mutations.
For homozygous amorphic alleles of Dmel\Trpml, pupal lethality is not complete, which allows assessment of phenotypes at the adult stage. The occasional adult escapers exhibit significantly reduced locomotor activity; brain biopsies reveal accumulations of late-apoptotic cells. Phenotypic assays using the fly gene have allowed characterization of genetic interactions; see the Trpml gene report.
NOTE: In the D. melanogaster sequenced strain (iso-1) there is a large tandem duplication in the region of Trpml that includes a second copy of this gene (CG42638).
[updated Apr. 2017 by FlyBase; FBrf0222196]
[MUCOLIPIDOSIS IV; ML4](https://omim.org/entry/252650)
[MUCOLIPIN 1; MCOLN1](https://omim.org/entry/605248)
Mucolipidosis IV is a lysosomal storage disorder characterized by psychomotor retardation (delayed development of mental and motor skills) and ophthalmologic abnormalities, including progressive corneal clouding and retinal degeneration. [from MIM:252650; 2015.12.22]
Most of the disease-causing lesions in MCOLN1 that have been characterized result in production of a disfunctional (often truncated) protein. [from Genetics Home Reference, MCOLN1; 2015.12.22]
ML4 is inherited as an autosomal recessive; it is associated with homozygous or compound heterozygous mutation in the Mucolipin 1 (MCOLN1) gene. Mucolipin 1 is also known as TRPML1, Transient Receptor Potential Cation Channel, Mucolipin subfamily, 1. [from MIM:252650, MIM:605248; 2015.12.22]
ML4 results from a defect in transport along the lysosomal pathway, affecting membrane sorting and/or late steps of endocytosis, which causes intracellular accumulation of lysosomal substrates. [from MIM:252650; 2015.12.22]
The MCOLN1 protein is a type of transient-receptor-potential cation channel and is found in the membranes of lysosomes and endosomes. [from Genetics Home Reference, MCOLN1; 2015.12.22] It is probably plays a role in the endocytic pathway and in the control of membrane trafficking of proteins and lipids. [from UniProt:Q9GZU1; 2015.12.22]
Many to one: 3 human to 1 Drosophila. Three human genes, MCOLN1, MCOLN2, MCOLN3, share orthology with the Drosophila gene, Dmel\Trpml. In the D. melanogaster sequenced strain (iso-1), a 26-kb region including the Trpml gene has been duplicated, producing an identical copy of Trpml that has been given the symbol Dmel\CG42638.
Ortholog of human MCOLN1, MCOLN2 and MCOLN3 (1 Drosphila to 3 human). Dmel\Trpml shares 41% identity and 60% similarity with human MCOLN3; 38% identity and 60% similarity with human MCOLN2; and 37% identity and 56% similarity with human MCOLN1.
