GeneBe

MCOLN1

protein-coding

mucolipin TRP cation channel 1, the group of Transient receptor potential cation channels

Gene summary

This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV. [provided by RefSeq, Oct 2009]

MANE transcript

NM_020533.3

Inheritance

AR, AD

ClinVar variants

P:168U:172B:383

Top phenotype

Corneal dystrophy, Lisch epithelial; Mucolipidosis IV

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr19:7,522,624-7,534,009

External References & Databases

Ensembl (ENSG00000090674)NCBI Gene (57192)OMIM (605248)HGNC:13356GenCCUniProt (Q9GZU1)AlphaFoldClinVar (MCOLN1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mucolipidosis type IVDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009653

Submitter: Ambry Genetics

mucolipidosis type IVSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009653

Submitter: Labcorp Genetics (formerly Invitae)

mucolipidosis type IVSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009653

Submitter: Orphanet

mucolipidosis type IVDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009653

Submitter: Myriad Women's Health

mucolipidosis type IVDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009653

Submitter: Natera

mucolipidosis type IVSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009653

Submitter: PanelApp Australia

Lisch epithelial corneal dystrophyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0010425

Submitter: Ambry Genetics

mucolipidosis type IVSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009653

Submitter: Genomics England PanelApp

Lisch epithelial corneal dystrophySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010425

Submitter: PanelApp Australia

mucolipidosis type IVDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009653

Submitter: ClinGen

The relationship between the MCOLN1 gene and mucolipidosis type IV (ML4), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 10, 2022. MCOLN1 encodes mucolipin-1, a cation channel that is involved in lysosomal exocytosis, a calcium-dependent process where endosomes fuse with lysosomes, and then fuse with the plasma membrane, via mediating intracellular calcium concentrations through its role as a calcium channel (PMID: 15336987). Among patients with ML4, impaired mucolipin-1 function results in impaired lysosomal exocytosis (PMID: 16914343), leading to disease manifestations which include neurodegeneration with psychomotor retardation, ophthalmologic anomalies, and achlorhydria (as reviewed in PMID: 32604955, PMID: 21763169, PMID: 12182165). The disease mechanism of ML4 is loss of function. ML4 was first reported by Berman et al. in 1974 (PMID: 4365943) and the first report of biallelic variants in MCOLN1 among ML4 patients was by Bargal et al. in 2000 (PMID: 10973263). Both case-level (genetic) and experimental evidence support the relationship between MCOLN1 and ML4. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 10973263, PMID: 11030752, PMID: 15523648, PMID: 31899079, PMID: 18326692). In total, eleven variants from six probands in five publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between MCOLN1 and ML4 includes: the biochemical function of the gene product (mucolipin-1) being consistent with the clinical and biochemical findings identified in individuals with ML4 (PMID: 15336987, PMID: 16914343, PMID: 32604955, PMID: 21763169, PMID: 12182165); the biochemical and clinical features of MCOLN1 knockout mice (PMID: 17924347); and rescue of neurologic impairment and neuronal accumulation of undegraded lysosomal substrates via adenovirus -mediated gene therapy in MCOLN1 knockout mice (PMID: 29788236). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, MCOLN1 is definitively associated with ML4. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 14, 2022 (SOP v9).

mucolipidosis type IVDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009653

Submitter: G2P

Clinical Genomic Database (CGD)

Corneal dystrophy, Lisch epithelial; Mucolipidosis IVAD/AR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 4365943; 166049; 7114093; 3918453; 2438637; 1789285; 9323557; 9600972; 9710036; 10973263; 11030752; 15523648; 17239335; 19006653; 20159435; 37972748Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MCOLN1 variants in ClinVar

21 Conditions Cataloged
Mucolipidosis type IVTotal: 916
Inborn genetic diseasesTotal: 117
not providedTotal: 82
not specifiedTotal: 34
Lisch epithelial corneal dystrophyTotal: 27
MCOLN1-related disorderTotal: 17
MCOLN1-related disordersTotal: 2
Growth delayTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020533.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
9
clinvar
348
clinvar
 358
missense
1
clinvar
10
clinvar
156
clinvar
32
clinvar
1
clinvar
 200
nonsense
14
clinvar
19
clinvar
2
clinvar
 35
start loss
2
clinvar
 2
frameshift
53
clinvar
31
clinvar
4
clinvar
 88
splice donor/acceptor (+/-2bp)
8
clinvar
29
clinvar
1
clinvar
2
clinvar
 40
Total78901723821723

Highest pathogenic variant AF is 0.00010472489

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_020533.3RefSeqNP_065394.114MANE Select
ENST00000264079.11EnsemblENSP00000264079.514MANE Select
ENST00000599334.1EnsemblENSP00000472176.16Standard
ENST00000601003.1EnsemblENSP00000469074.15Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
mcoln1aDanio rerio

Structure: cornea

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Iron metabolism in placenta
  • Transferrin endocytosis and recycling
  • Stimuli-sensing channels
  • Ion channel transport

Biological Process

  • adaptive immune response
  • cation transport
  • calcium-mediated signaling
  • transferrin transport
  • iron ion transmembrane transport

Molecular Function

  • cation channel activity
  • calcium channel activity
  • iron ion transmembrane transporter activity
  • protein binding
  • lipid binding

Cellular Component

  • phagocytic cup
  • lysosome
  • lysosomal membrane
  • late endosome
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000264079
Coding exons
14
Length
11384
Individuals with no LoFs
125655
Homozygous LoFs
0
Heterozygous LoFs
93
Defined
125748
p
0.000370
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.612723580.7600.00002643769
Missense (PolyPhen)98150.430.651471738
Synonymous-1.521871621.150.00001291199
Loss of Function3.231130.10.3650.00000176318

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish0.00430.0043notable
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.000320.00032rare
South Asian0.000200.00020rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis. Proposed to play a major role in Ca(2+) release from late endosome and lysosome vesicles to the cytoplasm, which is important for many lysosome-dependent cellular events, including the fusion and trafficking of these organelles, exocytosis and autophagy (PubMed:11013137, PubMed:12459486, PubMed:15336987, PubMed:14749347, PubMed:29019983). Required for efficient uptake of large particles in macrophages in which Ca(2+) release from the lysosomes triggers lysosomal exocytosis. May also play a role in phagosome-lysosome fusion (By similarity). Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events (PubMed:16978393). By mediating lysosomal Ca(2+) release is involved in regulation of mTORC1 signaling and in mTOR/TFEB- dependent lysosomal adaptation to environmental cues such as nutrient levels (PubMed:27787197, PubMed:25733853). Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS- induced TFEB activation and autophagy (PubMed:27357649). Functions as a Fe(2+) permeable channel in late endosomes and lysosomes (PubMed:18794901). Proposed to play a role in zinc homeostasis probably implicating its association with TMEM163 (PubMed:25130899) In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (By similarity). {ECO:0000250|UniProtKB:Q99J21, ECO:0000269|PubMed:12459486, ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:15336987, ECO:0000269|PubMed:16978393, ECO:0000269|PubMed:18794901, ECO:0000269|PubMed:25130899, ECO:0000269|PubMed:25733853, ECO:0000269|PubMed:27357649, ECO:0000269|PubMed:27787197, ECO:0000269|PubMed:29019983, ECO:0000305|PubMed:11013137}.;
Disease
DISEASE: Mucolipidosis 4 (ML4) [MIM:252650]: An autosomal recessive lysosomal storage disorder characterized by severe psychomotor retardation and ophthalmologic abnormalities, including corneal opacity, retinal degeneration and strabismus. Storage bodies of lipids and water-soluble substances are seen by electron microscopy in almost every cell type of the patients. Most patients are unable to speak or walk independently and reach a maximal developmental level of 1-2 years. All patients have constitutive achlorhydia associated with a secondary elevation of serum gastrin levels. {ECO:0000269|PubMed:10973263, ECO:0000269|PubMed:11013137, ECO:0000269|PubMed:11030752, ECO:0000269|PubMed:11317355, ECO:0000269|PubMed:12182165, ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:15178326, ECO:0000269|PubMed:15523648, ECO:0000269|PubMed:16978393, ECO:0000269|PubMed:18794901, ECO:0000269|PubMed:21256127, ECO:0000269|PubMed:28112729}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.172

Intolerance Scores

LoFtool
0.270
RVIS EVS
-0.93
RVIS percentile EVS
9.61

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.957

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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