DNAJC19 and 3‑methylglutaconic aciduria type 5

DNAJC19, a gene encoding a mitochondrial inner membrane chaperone, has been robustly linked to 3‑methylglutaconic aciduria type 5, a syndrome characterized by dilated cardiomyopathy, ataxia, and various metabolic disturbances. Multiple case reports describe patients with early onset cardiomyopathy, ataxia, microcytic anemia, and additional features such as genital anomalies and growth delay. These clinical findings consistently correlate with a deficiency in DNAJC19 function (PMID:22797137).

The condition follows an autosomal recessive inheritance pattern with clear segregation of pathogenic variants within affected families. In several reports, siblings or extended family members present with overlapping phenotypes, reinforcing the causal link between DNAJC19 mutations and the disease. For instance, the discovery of a homozygous single nucleotide deletion and other loss‐of‑function variants has provided compelling familial segregation evidence (PMID:27426421).

Genetic evidence is extensive and diverse. Multiple pathogenic variant types including nonsense, frameshift, and splice site mutations have been reported. A representative variant, c.250C>T (p.Arg84Ter), has been identified in several probands and underscores the disruptive effect leading to premature protein termination. These findings are supported by detailed variant analyses in independent cohorts, thereby reinforcing the genetic basis of the syndrome (PMID:35611801).

Functional studies further support the pathogenicity of DNAJC19 mutations. Experimental models including patient‑derived induced pluripotent stem cells and gene‑edited cell lines reveal mitochondrial fragmentation, increased respiration rates, and abnormal calcium kinetics. These alterations in mitochondrial function parallel the clinical manifestations observed in affected individuals, offering mechanistic insights into disease pathogenesis (PMID:38142971; PMID:22031295).

No significant conflicting evidence has been reported, and the converging genetic and functional data establish a strong association between DNAJC19 mutations and 3‑methylglutaconic aciduria type 5. Multi‐patient studies, including those in specific founder populations, have further confirmed the reproducibility of these findings across diverse ethnic groups (PMID:16055927; PMID:32521499).

In summary, the integration of robust genetic data with concordant functional evidence supports a strong gene‑disease association. This rigorous evaluation not only enhances diagnostic decision‑making but also provides a validated framework for the development of commercial genetic assays. Key take‑home: DNAJC19 mutation analysis is an essential tool for the accurate diagnosis and effective management of patients with 3‑methylglutaconic aciduria type 5.

References

• Pediatric research • 2012 • New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies PMID:22797137
• Pediatric neurology • 2016 • Progressive Cerebellar Atrophy and a Novel Homozygous Pathogenic DNAJC19 Variant as a Cause of Dilated Cardiomyopathy Ataxia Syndrome PMID:27426421
• Molecular genetics & genomic medicine • 2022 • Novel homozygous pathogenic mitochondrial DNAJC19 variant in a patient with dilated cardiomyopathy and global developmental delay PMID:35611801
• Case reports in genetics • 2024 • Genital Abnormalities and Growth Retardation as Early Signs of Dilated Cardiomyopathy with Ataxia Syndrome PMID:38283849
• Journal of medical genetics • 2006 • Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co‑chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome‑like condition PMID:16055927
• Stem cell research • 2020 • Generation of two patient‑derived iPSC lines from siblings and a genetically modified iPSC line to mimic dilated cardiomyopathy with ataxia caused by a homozygous DNAJC19 mutation PMID:32521499
• Molecular biology of the cell • 2011 • Reevaluation of the role of the Pam18:Pam16 interaction in translocation of proteins by the mitochondrial Hsp70‑based import motor PMID:22031295
• Molecular metabolism • 2024 • Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC‑derived cardiomyocytes PMID:38142971
• Stem cell research • 2024 • Generation of a homozygous DNAJC19 knockout human embryonic stem cell line by CRISPR/Cas9 system PMID:38696852

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