ISCU – Hereditary myopathy with lactic acidosis

ISCU (HGNC:29882) is robustly associated with hereditary myopathy with lactic acidosis (MONDO_0009706), a condition characterized by exercise intolerance, ptosis, dyspnea, palpitations, and lactic acidosis. The clinical features often include early-onset fatigue and episodic muscle weakness that can lead to life‐threatening metabolic crises, emphasizing the importance of molecular diagnosis for proper patient management (PMID:29079705).

Genetic evidence arises from multiple case reports. One study documented a de novo heterozygous missense mutation, c.287G>T (p.Gly96Val), identified in a single affected individual showing a mitochondrial myopathy phenotype reminiscent of the recessive disorder (PMID:29079705). In a separate report, classical recessively inherited cases were described in Swedish patients carrying a deep intronic splicing mutation that leads to aberrant transcript processing, with a compound heterozygous situation observed in a Scandinavian family (PMID:22155317).

Segregation analyses in these reports, while limited, include evidence within a familial context demonstrating co‐segregation of the mutant allele with disease in the compound heterozygous case (PMID:22155317).

The variant spectrum underlying ISCU deficiency includes both missense and splicing variants. The de novo missense allele c.287G>T (p.Gly96Val) serves as a representative example, while deep intronic and splice‐affecting mutations further substantiate the genetic heterogeneity of this disorder. These observations reflect a scenario where different mutation types disrupt iron–sulfur cluster assembly, leading to mitochondrial dysfunction.

Functional studies have provided significant experimental evidence supporting the pathogenicity of ISCU mutations. Multiple assays, including yeast models and patient fibroblast analyses, demonstrate that aberrant splicing events and missense changes result in defective assembly of iron–sulfur clusters, which impairs mitochondrial respiratory chain function. In particular, studies have revealed that splicing factors such as PTBP1 can repress the defective splicing caused by intronic mutations, while IGF2BP1 can reverse this repression (PMID:22125086; PMID:25447544).

It is noteworthy that although the majority of the evidence supports an autosomal recessive inheritance, the identification of a de novo dominant mutation expands the allelic spectrum and suggests the possibility of a dominant‐negative mechanism in select cases. The presence of both recessive and dominant effects within different contexts reinforces the overall strong gene–disease association, while also highlighting the need for careful genetic and clinical correlation.

In conclusion, the combined genetic findings from case reports, segregation analysis, and multiple functional assessments strongly support a role for ISCU in the pathogenesis of hereditary myopathy with lactic acidosis. Recognition of the ISCU variant spectrum and its functional consequences is critical for diagnostic decision‑making, therapeutic considerations, and ongoing research into mitochondrial disorders.

References

• Journal of Medical Genetics • 2017 • A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy PMID:29079705
• Gene • 2012 • Antisense oligonucleotide corrects splice abnormality in hereditary myopathy with lactic acidosis PMID:22155317
• Human Mutation • 2012 • The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be derepressed by IGF2BP1 PMID:22125086
• Biochimica et Biophysica Acta • 2015 • Anatomy of an iron-sulfur cluster scaffold protein: Understanding the determinants of [2Fe-2S] cluster stability on IscU PMID:25447544

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