MICU1

protein-coding

mitochondrial calcium uptake 1, the group of EF-hand domain containing

Gene summary

This gene encodes an essential regulator of mitochondrial Ca2+ uptake under basal conditions. The encoded protein interacts with the mitochondrial calcium uniporter, a mitochondrial inner membrane Ca2+ channel, and is essential in preventing mitochondrial Ca2+ overload, which can cause excessive production of reactive oxygen species and cell stress. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2013]

Previous symbols:

CBARA1

MANE transcript

NM_001195518.2

Inheritance

ClinVar variants

P:43U:107B:73

Top phenotype

Myopathy with extrapyramidal signs

gnomAD constraint

pLI —, LoF o/e 0.9

Max pathogenic AF

—

Genomic locus

chr10:72,367,340-72,626,131

External References & Databases

Ensembl (ENSG00000107745)

Transcript & Mutation Effects

hg38 • Region Span ~258.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

proximal myopathy with extrapyramidal signsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014300

Submitter: PanelApp Australia

proximal myopathy with extrapyramidal signsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014300

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

proximal myopathy with extrapyramidal signsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014300

Submitter: G2P

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MICU1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2023. *MICU1* encodes mitochondrial calcium uptake protein 1. This is a key regulator of the mitochondrial calcium uniporter (MCU), a multi-subunit calcium channel of the mitochondrial inner membrane. MICU1 senses calcium levels via its EF-hand domains. *MICU1* was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 24336167). While various names have been given to the constellation of features seen in those with *MICU1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MICU1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the relationship between *MICU1* and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation included two nonsense variants and two splicing / frameshift variants resulting in truncation observed in four probands in three publications (PMIDs: 24336167, 29721912, 33969448). All cases included in this curation were homozygous for the variant, and parents were confirmed carriers. There are additional cases reported in the medical literature (PMIDs: 33428302, 32395406, 36425804, 27123478), including individuals with exonic level deletions, however these were not included in this curation as the maximum genetic evidence score was reached. Age of onset is typically in early childhood but can also be seen up to adulthood. Clinical features in affected individuals include myopathy, developmental delay, ataxia, extrapyramidal signs, chorea, tremor, dystonia, microcephaly, neuropathy, optic atrophy, and ophthalmoplegia. The mechanism of disease is loss of function. This gene-disease association is also supported by a expression in brain and muscle, and several mouse models showing the impact of *MICU1* knockout on mitochondrial calcium uptake (PMIDs: 24336167, 27477272, 35302860). In summary, there is definitive evidence to support the relationship between *MICU1* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 20, 2023 (SOP Version 9).

proximal myopathy with extrapyramidal signsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014300

Submitter: Labcorp Genetics (formerly Invitae)

proximal myopathy with extrapyramidal signsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014300

Submitter: Ambry Genetics

proximal myopathy with extrapyramidal signsSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014300

Submitter: Orphanet

Clinical Genomic Database (CGD)

Myopathy with extrapyramidal signsAR

Manifestation: Musculoskeletal; Neurologic

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: 24336167; 27123478; 29721912

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MICU1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 281

Inborn genetic diseasesTotal: 49

Proximal myopathy with extrapyramidal signsTotal: 20

MICU1-related disorderTotal: 17

not specifiedTotal: 11

Neurodevelopmental disorderTotal: 2

Abnormality of the nervous systemTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001195518.2. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	69 clinvar	1 clinvar	72
missense		1 clinvar	104 clinvar	2 clinvar	1 clinvar	108
nonsense	10 clinvar	3 clinvar				13
start loss		1 clinvar				1
frameshift	10 clinvar	5 clinvar				15
splice donor/acceptor (+/-2bp)	2 clinvar	11 clinvar	1 clinvar			14
Total	22	21	107	71	2	223

Highest pathogenic variant AF is 0.00014505025

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 87 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001195518.2	RefSeq	NP_001182447.1	11	MANE Select
ENST00000361114.10	Ensembl	ENSP00000354415.5	11	MANE Select
NM_001195519.2	RefSeq	NP_001182448.1	7	Standard
NM_001363513.2	RefSeq	NP_001350442.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transport of small molecules
Mitochondrial calcium ion transport
Processing of SMDT1

Biological Process

mitochondrial calcium ion transmembrane transport
defense response
calcium import into the mitochondrion
protein homooligomerization
mitochondrial calcium ion homeostasis

Molecular Function

calcium ion binding
protein binding
identical protein binding
protein heterodimerization activity

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial intermembrane space
integral component of mitochondrial membrane
calcium channel complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361114
Coding exons: 11
Length: 258802
Individuals with no LoFs: 124581
Homozygous LoFs: 0
Heterozygous LoFs: 63
Defined: 124644
p: 0.000253

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.65	174	247	0.704	0.0000130	3145
Missense (PolyPhen)		31	67.052	0.46233		844
Synonymous	0.839	73	82.7	0.883	0.00000402	873
Loss of Function	0.465	21	23.4	0.896	0.00000145	280

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00019	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000056	0.000056	rare
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.00029	0.00027	rare
South Asian	0.00053	0.00052	rare
Other	0.00019	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key regulator of mitochondrial calcium uniporter (MCU) that senses calcium level via its EF-hand domains (PubMed:20693986, PubMed:23101630, PubMed:23747253, PubMed:24313810, PubMed:24332854, PubMed:24503055, PubMed:24560927, PubMed:26341627, PubMed:26903221, PubMed:27099988). MICU1 and MICU2 form a disulfide-linked heterodimer that stimulates and inhibits MCU activity, depending on the concentration of calcium. MICU1 acts both as an activator or inhibitor of mitochondrial calcium uptake (PubMed:26903221). Acts as a gatekeeper of MCU at low concentration of calcium, preventing channel opening (PubMed:26903221). Enhances MCU opening at high calcium concentration, allowing a rapid response of mitochondria to calcium signals generated in the cytoplasm (PubMed:24560927, PubMed:26903221). Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake (PubMed:22904319). Induces T-helper 1-mediated autoreactivity, which is accompanied by the release of IFNG (PubMed:16002733). {ECO:0000269|PubMed:16002733, ECO:0000269|PubMed:20693986, ECO:0000269|PubMed:22904319, ECO:0000269|PubMed:23101630, ECO:0000269|PubMed:23747253, ECO:0000269|PubMed:24313810, ECO:0000269|PubMed:24332854, ECO:0000269|PubMed:24503055, ECO:0000269|PubMed:24560927, ECO:0000269|PubMed:26341627, ECO:0000269|PubMed:26903221, ECO:0000269|PubMed:27099988}.;
Disease: DISEASE: Myopathy with extrapyramidal signs (MPXPS) [MIM:615673]: An autosomal recessive disorder characterized by early-onset proximal muscle weakness with a static course and moderately to grossly elevated serum creatine kinase levels accompanied by learning difficulties. Most patients develop subtle extrapyramidal motor signs that progress to a debilitating disorder of involuntary movement with variable features, including chorea, tremor, dystonic posturing and orofacial dyskinesia. Additional variable features include ataxia, microcephaly, ophthalmoplegia, ptosis, optic atrophy and axonal peripheral neuropathy. {ECO:0000269|PubMed:24336167}. Note=The disease is caused by mutations affecting the gene represented in this entry. The complex phenotype is due to alterations in mitochondrial calcium signaling characterized by increased mitochondrial Ca(2+) load (PubMed:24336167). {ECO:0000269|PubMed:24336167}.; DISEASE: Note=An homozygous partial MICU1 deletion is responsible for a disorder manifesting in childhood with fatigue, lethargy and muscle weakness. The disease is caused by mutations affecting the gene represented in this entry. {ECO:0000269|PubMed:27123478}.;

Recessive Scores

pRec: 0.158

Intolerance Scores

RVIS EVS: -0.45
RVIS percentile EVS: 24.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium