IARS2 – Leigh syndrome

The mitochondrial isoleucyl-tRNA synthetase gene IARS2 encodes an essential enzyme for mitochondrial protein synthesis. Pathogenic variants in IARS2 disrupt mitochondrial translation fidelity, leading to bioenergetic failure and early-onset neurodegeneration characteristic of Leigh syndrome.

Leigh syndrome due to IARS2 follows an autosomal recessive inheritance pattern. To date, five affected probands from four unrelated families have been reported, including a Chinese infant with West and Leigh syndromes (compound heterozygous c.2450G>A) ([PMID:38229969]), two Japanese siblings with infantile spasms and basal ganglia lesions carrying c.680T>C and c.2450G>A ([PMID:30041933]), and two unrelated Chinese boys with biallelic c.1_390del/c.2450G>A and c.2090G>A/c.2122G>A combinations ([PMID:39169373]).

The variant spectrum in IARS2–Leigh syndrome includes recurrent missense changes (c.2450G>A (p.Arg817His)) and early truncating alleles (c.1_390del). c.2450G>A has been observed in three families and likely affects the catalytic domain. Additional missense variants such as c.2090G>A (p.Arg697His) and c.2122G>A (p.Glu708Lys) expand allelic heterogeneity.

Functional studies in patient-derived lymphocytes and IARS2-knockdown HEK293T cells demonstrated combined deficiencies of mitochondrial complexes I and III, decreased oxygen consumption, reduced ATP production, and dissipation of mitochondrial membrane potential. Re-expression of wild-type IARS2 rescued these defects, confirming pathogenicity and implicating loss-of-function as the disease mechanism ([PMID:39169373]).

Segregation analysis in the Japanese sibship confirmed compound heterozygosity in both affected children with parental carrier status, supporting autosomal recessive transmission (1 additional affected relative) ([PMID:30041933]).

Integration of genetic and experimental data establishes a Strong clinical validity for IARS2 in Leigh syndrome. Biallelic IARS2 variants consistently result in mitochondrial respiratory chain dysfunction correlating with early neurodegeneration. Key take-home: IARS2 should be included in diagnostic gene panels for early-onset Leigh syndrome to enable accurate genetic counseling and potential targeted interventions.

References

• Global medical genetics • 2024 • A Pair of Compound Heterozygous IARS2 Variants Manifesting West Syndrome and Electrolyte Disorders in a Chinese Patient. PMID:38229969
• Brain & development • 2018 • Novel IARS2 mutations in Japanese siblings with CAGSSS, Leigh, and West syndrome. PMID:30041933
• Orphanet journal of rare diseases • 2024 • IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency. PMID:39169373
• Clinical genetics • 2020 • Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes. PMID:32020600

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