NDUFB3 – Mitochondrial Complex I Deficiency

NDUFB3 encodes a mitochondrial complex I subunit essential for assembly and electron transport. Autosomal recessive variants in NDUFB3 have been linked to isolated mitochondrial complex I deficiency (mitochondrial complex I deficiency).

In a cohort of 10 patients from 8 families with short stature and distinctive facial features, a recurrent homozygous missense variant c.64T>C (p.Trp22Arg) was identified, especially in individuals of Irish ancestry (PMID:27091925). An independent exome study uncovered a third case with compound heterozygous NDUFB3 variants, including a frameshift c.117del (p.Gly40_Leu41insTer) and a nonsense c.208G>T (p.Gly70Ter) (PMID:22499348).

All affected individuals exhibit biallelic variants consistent with autosomal recessive inheritance. Segregation analysis demonstrated homozygosity for p.Trp22Arg in 8 unrelated families, with at least 2 sib pairs confirming co-segregation of the variant with disease (PMID:27091925).

The variant spectrum comprises a recurrent missense (p.Trp22Arg), a frameshift (c.117del (p.Gly40_Leu41insTer)), and a premature termination codon (p.Gly70Ter), all predicted to ablate NDUFB3 function.

Functional assays in patient fibroblasts showed that expression of wild-type NDUFB3 cDNA rescued complex I activity and assembly defects caused by the p.Trp22Arg variant (PMID:22499348). Complementary skeletal muscle studies confirmed impaired complex I assembly in individuals homozygous for p.Trp22Arg (PMID:27091925).

Together, these genetic and experimental data provide strong evidence for NDUFB3 haploinsufficiency as a cause of autosomal recessive mitochondrial complex I deficiency.

Key take-home: Screening for the recurrent c.64T>C (p.Trp22Arg) NDUFB3 variant in patients with suggestive clinical features, particularly of Irish descent, can expedite genetic diagnosis without requiring muscle biopsy.

References

• Journal of medical genetics • 2012 • Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. PMID:22499348
• Journal of medical genetics • 2016 • A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype. PMID:27091925

Evidence Based Scoring (AI generated)