Abstract
Runting and stunting syndrome (RSS), which is characterized by low body weight, generally occurs early in life and leads to considerable economic losses in the commercial broiler industry. Our previous study has suggested that RSS is associated with mitochondria dysfunction in sex-linked dwarf (SLD) chickens. However, the molecular mechanism of RSS remains unknown. Based on the molecular diagnostics of mitochondrial diseases, we identified a recessive mutation c. 409G > A (p. Ala137Thr) of Twinkle mitochondrial DNA helicase (TWNK) gene and mitochondrial DNA (mtDNA) depletion in RSS chickens’ livers from strain N301. Bioinformatics investigations supported the pathogenicity of the TWNK mutation that is located on the extended peptide linker of Twinkle primase domain and might further lead to mtDNA depletion in chicken. Furthermore, overexpression of wild-type TWNK increases mtDNA copy number, whereas overexpression of TWNK A137T causes mtDNA depletion in vitro. Additionally, the TWNK c. 409G > A mutation showed significant associations with body weight, daily gain, pectoralis weight, crureus weight, and abdominal fat weight. Taken together, we corroborated that the recessive TWNK c. 409G > A (p. Ala137Thr) mutation is associated with RSS characterized by mtDNA depletion in SLD chicken.
Highlights
Runting and stunting syndrome (RSS) in chicken generally occurs early in life and leads to considerable economic losses through decreased body weight, in the commercial broiler industry (Kang et al, 2012)
The results revealed that the relative mitochondrial DNA (mtDNA) copy number for the RSS chickens was 56% lower than that for the normal sex-linked dwarf (SLD) chickens as evaluated by the change of tRNA-Leu and 52% lower as evaluated by the change of rRNA-16S (Figure 2C)
The mutations in many genes are associated with early onset hepatocerebral mtDNA depletion syndromes (MDS), including POLG (Naviaux and Nguyen, 2004), Twinkle mitochondrial DNA helicase (TWNK) (Sarzi et al, 2007), TK2 (Zhang et al, 2010), DGUOK (Mandel et al, 2001), and MPV17 (Wong et al, 2007)
Summary
Runting and stunting syndrome (RSS) in chicken generally occurs early in life and leads to considerable economic losses through decreased body weight, in the commercial broiler industry (Kang et al, 2012). Our previous study has suggested that RSS is associated with mitochondria dysfunction in sex-linked dwarf (SLD) chickens, and we TWNK Gene Mutation Causes MDS postulated that the mitochondrial dysfunction in RSS chickens is caused by nuclear gene mutations (Li et al, 2019). Similar to human mtDNA, chicken mtDNA encodes only 13 oxidative phosphorylation (OXPHOS) proteins, two rRNAs, and 22 tRNAs (Boore, 1999). Since the synthesis of mtDNA is essential for the subunits of OXPHOS proteins, insufficient mtDNA synthesis leads to organ dysfunction to trigger many syndromes in human (Spinazzola et al, 2009), such as mtDNA depletion syndromes (MDS), which are autosomal recessive disorders characterized by a reduction in mtDNA copy number in specific tissues (El-Hattab et al, 2017). A previous study has reported that an autosomal recessive mutation in TWNK is linked to MDS in human (Sarzi et al, 2007). Mitochondrial diseases caused by nuclear gene mutations have not been reported in poultry
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