DNAJB6 – Limb-Girdle Muscular Dystrophy Type 1D

Autosomal dominant limb-girdle muscular dystrophy type 1D (LGMD1D) is caused by heterozygous missense variants in the DNAJB6 gene, encoding an Hsp40 co-chaperone. Affected individuals present with progressive proximal muscle weakness, rimmed vacuoles on biopsy, and, in childhood-onset cases, dysphagia and hypernasal speech PMID:26371419, PMID:31034989. Age of onset ranges from childhood to late adulthood with marked intrafamilial variability.

Genetic evidence supports autosomal dominant inheritance. Four distinct missense mutations in the G/F domain (p.Phe89Ile, p.Phe89Leu, p.Phe93Leu) were identified in nine unrelated families across Finland, the United States, and Italy, with co-segregation in multiple affected members PMID:22366786. Case reports describe a novel c.271T>C (p.Phe91Leu) in a Korean pedigree with severe childhood onset [PMID:26371419] and c.271T>G (p.Phe91Val) in a late-onset mild family [PMID:31034989].

The variant spectrum is dominated by missense changes within the G/F domain, with occasional mutations in the J domain (e.g., c.149C>T (p.Ala50Val), c.161A>C (p.Glu54Ala)). The recurrent p.Phe93Leu allele appears in multiple populations [PMID:22366786]. The c.271T>C (p.Phe91Leu) variant is uniquely associated with a more severe, early-onset phenotype [PMID:26371419].

Functional studies demonstrate a toxic gain-of-function mechanism. Zebrafish embryos expressing p.Phe91Leu exhibit profound muscle defects compared to p.Phe93Leu and p.Pro96Arg controls [PMID:26371419]. Transgenic mice expressing p.Phe93Leu in the DNAJB6b isoform develop myofibrillar disorganization and desmin inclusions mirroring human pathology [PMID:26362252]. In vitro assays reveal prolonged DNAJB6 half-life, loss of anti-aggregation function, and unregulated interaction with Hsp70 chaperones [PMID:22366786].

No conflicting evidence disputing the primary association has been reported. Phenotypic variability suggests genetic or environmental modifiers may influence age of onset and severity [PMID:31034989].

Collectively, the concordant genetic and experimental data provide strong clinical validity for DNAJB6 in LGMD1D. DNAJB6 sequencing is recommended in individuals with dominantly inherited proximal or distal myopathy, rimmed vacuoles, or early respiratory and bulbar involvement. Key Take-home: Dominant missense variants in DNAJB6 cause LGMD1D via toxic gain-of-function and are actionable for molecular diagnosis and genetic counseling.

References

• Nature Genetics • 2012 • Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy PMID:22366786
• Neuromuscular Disorders • 2015 • A novel mutation in DNAJB6, p.(Phe91Leu), in childhood-onset LGMD1D with a severe phenotype. PMID:26371419
• European Journal of Medical Genetics • 2020 • Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type. PMID:31034989
• Human Molecular Genetics • 2015 • Myofibrillar disruption and RNA-binding protein aggregation in a mouse model of limb-girdle muscular dystrophy 1D. PMID:26362252
• The Journal of Biological Chemistry • 2014 • Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers. PMID:24920671

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