MICU1 – Proximal Myopathy with Extrapyramidal Signs

Myopathy with extrapyramidal signs (MPXPS) is an autosomal recessive mitochondrial disorder caused by biallelic loss-of-function mutations in the mitochondrial calcium uptake 1 gene (MICU1) (Gene Symbol; Disease Name). MICU1 encodes the gatekeeper of the mitochondrial Ca²⁺ uniporter, ensuring controlled calcium influx into the mitochondrial matrix. Disruption of this regulation leads to aberrant mitochondrial Ca²⁺ handling, elevated reactive oxygen species, and cellular energy deficits, particularly affecting muscle and extrapyramidal neurons.

Clinical Validity

MICU1–MPXPS meets a Strong ClinGen gene–disease association category based on homozygous LoF variants reported in 44 probands across multiple consanguineous families and evidence of segregation in at least 3 pedigrees (2 probands (PMID:32293312); 1 proband (PMID:37034047); +41 probands (PMID:33969448)). Functional studies are concordant with human phenotype.

Genetic Evidence

Inheritance mode: Autosomal recessive. Segregation: homozygous variants co-segregate with disease in consanguineous families. Case series describe 44 affected individuals with onset in childhood to early adulthood presenting with proximal muscle weakness, extrapyramidal movement disorders, and variable additional features (PMID:33969448).

Variant spectrum is exclusively loss-of-function, including:

• c.1296del (p.Glu432AspfsTer6) – frameshift leading to premature stop (PMID:32293312)
• c.1072-1G>C – canonical splice-site disruption (PMID:37034047)
• c.385C>T (p.Arg129Ter) – nonsense (PMID:33969448)

Functional Evidence

Homozygous deletion of exon 1 abolishes MICU1 protein in patient fibroblasts, causing impaired mitochondrial Ca²⁺ uptake that is fully rescued by wild-type MICU1 overexpression (PMID:27123478). Patient-derived fibroblasts with MICU1 mutations exhibit elevated resting mitochondrial Ca²⁺ concentration, futile Ca²⁺ cycling via NCLX, mitochondrial fragmentation, and altered bioenergetics, establishing the pathophysiological mechanism of MPXPS (PMID:28132899).

Integration & Clinical Utility

Biallelic LoF variants in MICU1 cause proximal myopathy with extrapyramidal signs via loss of mitochondrial Ca²⁺ gating. Genetic confirmation enables definitive diagnosis, informs reproductive counseling, and guides clinical management. Functional assays in patient cells corroborate pathogenicity and provide a model for future therapeutic screening.

Key Take-home: Autosomal recessive MICU1 LoF variants underlie MPXPS, and combined genetic and functional evidence robustly supports diagnostic testing for at-risk individuals.

References

• BMC medical genetics • 2020 • Reporting a rare form of myopathy, myopathy with extrapyramidal signs, in an Iranian family using next generation sequencing: a case report. PMID:32293312
• Annals of Indian Academy of Neurology • 2023 • Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India. PMID:37034047
• Molecular and cellular pediatrics • 2021 • Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family. PMID:33969448
• Neurology. Genetics • 2016 • Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood. PMID:27123478
• Biochimica et biophysica acta. Molecular cell research • 2017 • Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics. PMID:28132899

Evidence Based Scoring (AI generated)