NFU1 – Multiple Mitochondrial Dysfunctions Syndrome 1

Multiple mitochondrial dysfunctions syndrome 1 (MMDS1) is a rare, autosomal recessive disorder caused by bi-allelic mutations in the NFU1 gene (HGNC:16287). Patients present in infancy with fatal encephalopathy, lactic acidosis, hyperglycinemia, combined respiratory chain complex I–II deficiency, and in many cases severe pulmonary hypertension (PMID:31970900). Autopsy of affected siblings reveals developmental lung abnormalities that likely underlie early-onset pulmonary vascular disease.

Genetic evidence comprises 19 affected individuals from 10 unrelated families harboring compound heterozygous or homozygous NFU1 variants (PMID:36256512). The spectrum includes missense (e.g., c.622G>T (p.Gly208Cys)), splice-site (c.545+5G>A), frameshift (c.146del (p.Pro49LeufsTer8)), and deep-intronic alleles. The recurrent c.622G>T (p.Gly208Cys) variant appears in multiple populations and has been shown to abolish protein-bound lipoic acid and impair complex II assembly in patient fibroblasts (PMID:23179554). Segregation in consanguineous and non-consanguineous pedigrees confirms autosomal recessive inheritance.

Functional studies across species demonstrate concordant pathogenicity: patient fibroblast complementation rescues respiratory chain and 2-oxoacid dehydrogenase activities when wild-type NFU1 is expressed (PMID:21944046); yeast and human cell RNAi models show selective loss of lipoylated enzymes and succinate dehydrogenase; C. elegans CRISPR allelic series recapitulates mitochondrial respiratory dysfunction and oxidative stress (PMID:34449775); and a humanized rat NFU1G206C model develops pulmonary arterial hypertension with sex-specific penetrance mirroring the human phenotype (PMID:31461310).

Mechanistically, NFU1 functions as a late-acting iron-sulfur (Fe-S) cluster scaffold for a subset of mitochondrial Fe-S proteins, including lipoate synthase and succinate dehydrogenase. Loss-of-function variants disrupt cluster delivery, leading to deficient lipoylation and complex II assembly.

No studies have refuted NFU1 as the causative gene for MMDS1. The aggregate of genetic segregation, variant spectrum, and multi-model functional assays yields a robust gene-disease relationship.

Key Take-home: NFU1 loss-of-function mutations are a strong, clinically actionable cause of MMDS1, warranting early genetic testing in infants with unexplained lactic acidosis, hyperglycinemia, and pulmonary hypertension.

References

• American Journal of Medical Genetics Part A • 2020 • Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension. PMID:31970900
• American Journal of Human Genetics • 2011 • Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. PMID:21944046
• Journal of Inherited Metabolic Disease • 2013 • Protein expression profiles in patients carrying NFU1 mutations. Contribution to the pathophysiology of the disease. PMID:23179554
• PLoS Genetics • 2021 • Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in Caenorhabditis elegans. PMID:34449775
• American Journal of Respiratory Cell and Molecular Biology • 2020 • Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension. PMID:31461310

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