Alternative titles; symbols
HGNC Approved Gene Symbol: MCOLN1
SNOMEDCT: 724175002, 725296006; ICD10CM: E75.11;
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:7,522,624-7,534,009 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Lisch epithelial corneal dystrophy | 620763 | Autosomal dominant | 3 |
| Mucolipidosis IV | 252650 | Autosomal recessive | 3 |
By positional cloning of the mucolipidosis IV (ML4; 252650) locus on chromosome 19p, Bargal et al. (2000) identified a gene, designated MCOLN1, encoding a 580-amino acid protein termed mucolipin-1. The mucolipin-1 protein contains 1 transmembrane helix in the N-terminal region and at least 5 transmembrane domains in the C-terminal region.
Bassi et al. (2000) also identified the MCOLN1 gene, which they termed 'ML4.' The corresponding protein, which the authors called 'mucolipidin,' localizes on the plasma membrane and, in the carboxy-terminal region, shows homology to polycystin-2, the product of the polycystic kidney disease gene (PKD2; 173910), and to the family of transient receptor potential Ca(2+) channels (see 602343). They suggested that mucolipidin plays an important role in endocytosis.
Sun et al. (2000) independently cloned the MCOLN1 gene. The 65-kD protein contains a transient receptor potential (TRP) cation channel domain (amino acids 331-521) and an internal calcium and sodium channel pore region (amino acids 496-521). The TRP domain spans transmembrane segments 3-6, with the putative pore-forming loop between the fifth and sixth segments. There is also a dileucine motif at the C terminus which may serve as a late endosomal/lysosomal targeting motif. The protein is predicted to have both the N- and C-termini within the cytoplasm. Sun et al. (2000) suggested that mucolipin-1 may play a role in calcium ion transport.
Bargal et al. (2000) determined that the MCOLN1 gene contains 14 exons spanning approximately 14 kb.
By genomic sequence analysis, Bargal et al. (2000) mapped the MCOLN1 gene to chromosome 19p13.3-p13.2.
Cryoelectron Microscopy
Schmiege et al. (2017) reported 2 electron cryomicroscopy structures of full-length human TRPML1: a 3.72-angstrom apo structure at pH 7.0 in the closed state, and a 3.49-angstrom agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighboring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1 (602076), a TRP channel from a different subfamily.
Chen et al. (2017) presented the single-particle electron cryomicroscopy structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis analysis, the TRPML1 structure revealed that phosphatidylinositol 3,5-bisphosphate binds to the N terminus of the channel, distal from the pore, and the helix-turn-helix extension between segments S2 and S3 probably couples ligand binding to pore opening.
Lysosomal exocytosis is a calcium-dependent process in which late endosomes fuse with lysosomes, which then fuse to the plasma membrane. The local calcium source is the luminal compartment of the late endosome or lysosome itself. By in vitro electrophysiologic studies, LaPlante et al. (2002, 2004) identified mucolipin-1 as a calcium channel that could be transiently modulated by changes in calcium concentration. The channel was also permeable to sodium and potassium, and was detected both on intracellular vesicular membranes, including lysosomes, and on the plasma membrane. Fibroblasts derived from ML IV patients with mutations in the MCOLN1 gene showed disturbed calcium signaling, large acidic organelles, and decreased fusion between endosomes and lysosomes compared to wildtype cells. LaPlante et al. (2004) concluded that the MCOLN1 channel contributes to the increase in local concentrations of calcium during the transition between different stages in membrane trafficking. Cells with defects in the MCOLN1 channel cannot release enough calcium, resulting in slow and inefficient endosomal and lysosomal fusion and an abnormal accumulation of lipid and other materials as seen in ML IV.
Raychowdhury et al. (2004) assessed mucolipin-1 channel function from endosomal vesicles of null (MCOLN1 -/-) and mucolipin-1 over-expressing cells, and liposomes containing the in vitro translated protein. Evidence from both preparations indicated that the wildtype protein is a multiple subconductance nonselective cation channel whose function is inhibited by a reduction of pH. The V446L and F408del ML IV-causing mutations retained channel function but not the sharp inhibition by lowering pH. Atomic force imaging of mucolipin-1 channels indicated that changes in pH modified the aggregation of unitary channels. The mutant protein did not change in size on reduction of pH. Raychowdhury et al. (2004) concluded that mucolipin-1 channel activity is regulated by a pH-dependent mechanism that is deficient in some ML IV-causing mutations of the gene. They also suggested a role for cation channels in the acidification and normal endosomal function.
By transfecting human embryonic kidney cells with various combinations of mouse Trpml3 (MCOLN3; 607400), chicken Trpml2 (MCOLN2; 607399), and human TRPML1, Venkatachalam et al. (2006) showed that each TRPML could form homomultimers and heteromultimers with other TRPML proteins. When expressed individually, TRPML1 and Trpml2 were lysosomal membrane proteins, whereas Trpml3 was retained in the endoplasmic reticulum. In contrast, when Trpml3 was coexpressed with either TRPML1 or Trpml2, it relocalized to lysosomes. Mutation of the lysosomal targeting sequence of TRPML1 or Trpml2 or disruption of clathrin-mediated endocytosis caused mislocalization of TRPML1 and Trpml2 to the plasma membrane and also resulted in plasma membrane distribution of Trpml3. Trpml3 did not influence the intracellular localization of TRPML1 or Trpml2.
By measuring radiolabeled iron uptake, monitoring the levels of cytosolic and intralysosomal iron, and by directly patch-clamping the late endosomal and lysosomal membrane, Dong et al. (2008) showed that TRPML1 functions as a Fe(2+)-permeable channel in late endosomes and lysosomes. TRPML1 mutations resulting in ML IV (252650) impair the permeability of TRPML1 to Fe(2+) to varying degrees, which correlate well with disease severity. A comparison of TRPML1-null ML IV and control human skin fibroblasts showed a reduction in cytosolic Fe(2+) levels, an increase in intralysosomal Fe(2+) levels, and an accumulation of lipofuscin-like molecules in TRPML1-null cells. Dong et al. (2008) proposed that TRPML1 mediates a mechanism by which Fe(2+) is released from late endosomes and lysosomes. Dong et al. (2008) concluded that impaired iron transport may contribute to both hematologic and degenerative symptoms of ML IV patients.
Using yeast 2-hybrid and immunoprecipitation analyses, Cuajungco et al. (2014) showed that human TMEM163 interacted with TRPML1 and that the interaction required the N terminus of TMEM163. Confocal microscopy of human fibroblasts and HEK293 cells, revealed that human TMEM163 and TRPML1 colocalized in late endosomes or lysosomes. TMEM163 mRNA and protein were reduced in fibroblasts from patients with ML4, and the reduction in TMEM163 correlated with increased lysosomal zinc levels. Further analysis confirmed that interaction of TRPML1 with TMEM163 was important for maintaining cellular zinc homeostasis.
Mucolipidosis IV
In 21 Ashkenazi Jewish ML IV patients, Bargal et al. (2000) identified 2 mutations in the MCOLN1 gene (IVS3-2A-G, 605248.0001; 6,450-bp del, 605248.0002) that correlated with the major and minor haplotypes identified by Slaugenhaupt et al. (1999). Six patients were compound heterozygous for both mutations and 2 patients were compound heterozygous for 1 of the founder mutations and a second unidentified mutation. The clinical manifestations of all patients showed similar severity.
Bargal et al. (2001) identified 4 mutations in the MCOLN1 gene in severely affected patients with ML IV. An in-frame deletion (F408del) was identified in a patient with unusually mild psychomotor retardation. The frequency of ML IV in the general Jewish Ashkenazi population was estimated in a sample of 2,000 anonymous, unrelated individuals assayed for the 2 founder mutations. This analysis indicated a heterozygote frequency of about 1 in 100.
Edelmann et al. (2002) stated that the 2 common MCOLN1 mutations (IVS3-2A-G, 605248.0001; 511del6434, 605248.0002) accounted for more than 95% of the mutant alleles in the Ashkenazi Jewish population. In the greater New York metropolitan area, the frequency of the splice site mutation was 0.54% and of the deletion mutation 0.25%, for a combined carrier frequency of 0.79%, or 1 in 127 individuals. They suggested that the addition of both mutations be considered for prenatal carrier screening in this population.
Bach et al. (2005) found a carrier frequency of 0.0104 for ML IV in a population of 66,749 Ashkenazi Jewish subjects of the Dor Yeshorim program, a unique premarital population-screening program designed for the Orthodox Jewish community. The distribution of the 2 Ashkenazi Jewish founder mutations, IVS3-2A-G and del Ex1-Ex7, was determined to be 78.15% and 21.85%, respectively.
Lisch Epithelial Corneal Dystrophy
In 23 affected individuals from 13 families with Lisch epithelial corneal dystrophy (LECD; 620763), Patterson et al. (2024) identified heterozygosity for mutations in the MCOLN1 gene (see, e.g., 605248.0010 and 605248.0011), including 7 patients who were heterozygous for variants previously reported to cause ML4 in the biallelic state (see, e.g., 605248.0001). Incomplete penetrance was observed in 1 of the families, and review of 6 heterozygous carrier parents from 3 ML4 families did not show any evidence of LECD. Patterson et al. (2024) concluded that heterozygous MCOLN1 variants can be associated with incomplete penetrance of LECD, and estimated a penetrance of 0.2% for MCOLN1 loss-of-function variants based on the gnomAD database population sample. They suggested that such a low penetrance might support the hypothesis that LECD opacities are localized areas of cells with ML4 due to a somatic 'second hit' to the second MCOLN1 gene copy in those cells, which would be consistent with observed unilateral and sporadic cases.
Unlike other lysosomal storage diseases, ML IV is not associated with a lack of lysosomal hydrolases; instead, ML IV cells display abnormal endocytosis of lipids and accumulate large vesicles, indicating that a defect in endocytosis may underlie the disease. Fares and Greenwald (2001) reported the identification of a loss-of-function mutation in the Caenorhabditis elegans mucolipin-1 homolog, cup-5, and showed that this mutation resulted in an enhanced rate of uptake of fluid-phase markers, decreased degradation of endocytosed protein, and accumulation of large vacuoles. Overexpression of cup-5(+) caused the opposite phenotype, indicating that cup-5 activity controls aspects of endocytosis.
Venugopal et al. (2007) described a murine model for mucolipidosis type IV that accurately replicated the phenotypes of patients with the disorder. The Mcoln1 -/- knockout mice presented with numerous dense inclusion bodies in all cell types in brain and particularly in neurons, elevated plasma gastrin, vacuolization in gastric parietal cells, and retinal degeneration. Neurobehavioral assessments, including analysis of gait and clasping, confirmed the presence of a neurologic defect. Gait deficits progressed to complete hind-limb paralysis and death at approximately 8 months of age. The Mcoln1 -/- mice were born in mendelian ratios, and both male and female Mcoln1 -/- mice were fertile. A hallmark of human mucolipidosis IV is elevated plasma gastrin (Schiffmann et al., 1998), which can be increased up to 13 times that of normal. Serum gastrin in the knockout mice was significantly elevated compared with that in wildtype mice.
Using a Drosophila model of ML IV, Venkatachalam et al. (2008) found that vesicular accumulation of macromolecules was due to defective autophagy, which resulted in oxidative stress and impaired synaptic transmission. Late apoptotic cells accumulated in Trpml-mutant brains, and accumulation of apoptotic cells and motor deficits were suppressed by expression of wildtype Trpml in neurons, glia, or hematopoietic cells. Venkatachalam et al. (2008) concluded that the neurodegeneration and motor defects in this model of ML IV resulted primarily from decreased clearance of apoptotic cells.
Mucolipidosis IV
In 12 of 21 Ashkenazi Jewish patients with mucolipidosis IV (ML4; 252650) associated with the major Ashkenazi founder haplotype defined by Slaugenhaupt et al. (1999), Bargal et al. (2000) identified a homozygous A-to-G transition in the acceptor splice site of the third intron of the MCOLN1 gene. One heterozygote was found among 60 Ashkenazi normal controls; this was consistent with the estimated frequency of heterozygotes (1/50) in this population.
Bassi et al. (2000) identified this acceptor splice site mutation, which they designated c.486-2A-G, as the major founder mutation in Ashkenazi Jewish patients with ML4. The mutation disrupted the GT-AG rule of splicing and resulted in a transcript lacking 165 bp, because of the skipping of exon 4. This caused a frameshift leading to a premature translation termination 374 bp downstream. The predicted truncated protein retained only the first 21 amino acids of the wildtype protein.
Bargal et al. (2001) noted that Bassi et al. (2000) numbered the cDNA positions of the mutations from the transcript start, instead of from the initiator ATG, as recommended in Antonarakis (1998).
Lisch Epithelial Corneal Dystrophy
In 4 unrelated patients (LECD4, LECD5, LECD6, and LECD10) with Lisch epithelial corneal dystrophy (LECD; 620763), Patterson et al. (2024) identified heterozygosity for a splice site mutation in the MCOLN1 gene (c.406-2G-A, NM_020533.3).
In 1 of 21 Ashkenazi Jewish patients with mucolipidosis IV (ML4; 252650) associated with the minor founder haplotype defined by Slaugenhaupt et al. (1999), Bargal et al. (2000) identified a homozygous 6,450-bp deletion in the MCOLN1 gene. The deletion spanned a region from 928 bp upstream from the first exon of MCOLN1 to bp 31 of exon 7 (del EX1-EX7). The clinical manifestations for homozygotes for either this mutation or IVS3-2A-G (605248.0001), or compound heterozygotes, showed similar severity. Among 21 Ashkenazi ML4 patients, 12 were homozygous for the splice mutation, 1 was homozygous for the del EX1-EX7 mutation, and 6 were compound heterozygous. Two patients were compound heterozygous for 1 of these mutations and an unidentified second allele.
Bassi et al. (2000) demonstrated this deletion, which they measured to be 6,432 bp, spanning a region from the 5-prime end of the gene to exon 6, as the minor founder mutation in Ashkenazi Jewish patients with ML4.
Edelmann et al. (2002) referred to this mutation as 511del6434.
In an Arab-Druze mucolipidosis IV (ML4; 252650) patient, Bargal et al. (2000) identified a homozygous c.1048C-T transition in exon 8 of the MCOLN1 gene, resulting in an arg321-to-ter (R321X) mutation. The parents were first cousins and carried the same unique haplotype.
Bargal et al. (2001) noted that Bargal et al. (2000) numbered the cDNA positions of the mutations from the transcript start, instead of from the initiator ATG, as recommended in Antonarakis (1998). Bargal et al. (2001) gave the preferred designation of this mutation as c.964C-T, R322X.
In an Ashkenazi Jewish patient with mucolipidosis IV (ML4; 252650), Sun et al. (2000) identified compound heterozygosity for 2 mutations in the MCOLN1 gene: a 3-bp deletion eliminating codon 408 in the TRP cation channel domain, and the common splice site mutation (605248.0001).
In a non-Ashkenazi Jewish patient with mucolipidosis IV (ML4; 252650), Sun et al. (2000) identified compound heterozygosity for 2 mutations in the MCOLN1 gene: a c.1209G-T transversion resulting in an asp362-to-tyr (D362Y) substitution in the TRP cation channel domain, and a c.429C-T transition resulting in an arg102-to-ter (R102X; 605248.0006) termination codon.
In a non-Ashkenazi Jewish girl with ML4, Dobrovolny et al. (2007) identified compound heterozygosity for the D362Y substitution and a splice site mutation (605248.0009) in the MCOLN1 gene. In contrast to the report by Sun et al. (2000), they stated that the D362Y substitution is caused by a c.1084G-T transversion and that D362Y occurs in the third transmembrane region of the protein and leads to retention of the protein in the endoplasmic reticulum. The phenotype in the patient reported by Dobrovolny et al. (2007) was unusual in that the symptoms were restricted to the eyes, including corneal clouding and decreased visual acuity. She had no neurologic abnormalities.
For discussion of the arg102-to-ter (R102X) mutation in the MCOLN1 gene that was found in compound heterozygous state in a patient with mucolipidosis IV (ML4; 252650) by Sun et al. (2000), see 605248.0005.
Goldin et al. (2004) described a 4-year-old girl with mucolipidosis IV (ML4; 252650) who was compound heterozygous for 2 mutations in the MCOLN1 gene, only 1 of which, inherited from the father, was expressed. They found in her mucolipin-1 cDNA a 1207C-T transition predicting an arg403-to-cys (R403C) substitution, which changes a basic amino acid to a neutral one in the fourth transmembrane domain of mucolipin-1. From the mother, the patient had inherited a 93-bp segment from the mitochondrial NADH dehydrogenase-5 gene (MTND5; 516005) that was inserted in-frame prior to the last nucleotide of exon 2 of the MCOLN1 gene (236_237ins93; 605248.0008). This alteration abolished proper splicing of MCOLN1. The splice site at the end of the exon was not used due to an inhibitory effect of the inserted segment, resulting in 2 aberrant splice products containing stop codons in the downstream intron. These products were eliminated via nonsense-mediated decay. The authors stated that this was the first report of an inherited transfer of mitochondrial DNA causing a genetic disease. The elimination of a splice site by the mitochondrial DNA required a change in splicing prediction models.
For discussion of the 93-bp insertion in the MCOLN1 gene that was found in compound heterozygous state in a patient with mucolipidosis IV (ML4; 252650) by Goldin et al. (2004), see 252650.0007.
In a non-Ashkenazi Jewish girl with mucolipidosis IV (ML4; 252650), Dobrovolny et al. (2007) identified compound heterozygosity for 2 mutations in the MCOLN1 gene. One allele carried a c.1704A-T transversion near the 3-prime end of exon 13, resulting in erroneous splicing, a 4-bp deletion, and a predicted protein product with the last 12 amino acids exchanged for 9 different ones. Both normal and pathologic splice forms were detected in skin fibroblasts and leukocytes, with the normal form estimated at 40%, presumably enough to prevent psychomotor retardation. The other allele carried D362Y (605248.0005). The phenotype was unusual in that the symptoms were restricted to the eyes, including corneal clouding and decreased visual acuity. She had no neurologic abnormalities.
In 7 affected members of a large 6-generation German pedigree (LECD1) with Lisch epithelial corneal dystrophy (LECD; 620763), originally described by Lisch et al. (1992), Patterson et al. (2024) identified heterozygosity for a c.576C-A transversion (c.576C-A, NM_020533.3) in the MCOLN1 gene, resulting in a cys192-to-ter (C192X) substitution. The mutation segregated with disease in the family and was not found in the gnomAD database, but was present in a 64-year-old man who did not show signs of LECD, suggesting incomplete penetrance.
Mucolipidosis IV
In a non-Jewish family (family 53) with mucolipidosis IV (ML4; 252650), Sun et al. (2000) identified a c.639C-T transition in exon 4 of the MCOLN1 gene that resulted in an arg172-to-ter (R172X) substitution. The mutation occurred in compound heterozygosity with a splice site mutation.
Lisch Epithelial Corneal Dystrophy
In 4 affected individuals over 2 generations of a family (LECD2) with Lisch epithelial corneal dystrophy (LECD; 620763), Patterson et al. (2024) identified heterozygosity for a c.514C-T transition (c.514C-T, NM_020533.3) in the MCOLN1 gene, resulting in an R172X substitution.
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