Mutations in mitochondrial DNA causing tubulointerstitial kidney disease

Area of Science:

• Genetics
• Nephrology
• Mitochondrial Biology

Background:

• Tubulointerstitial kidney disease is a significant cause of kidney failure with unknown origins.
• Mitochondrial DNA (mtDNA) mutations are known to cause multi-organ diseases, but control region mutations' role was unclear.

Purpose of the Study:

• To investigate the genetic basis of maternally inherited tubulointerstitial kidney disease.
• To determine if mitochondrial DNA control region mutations cause kidney disease.

Main Methods:

• Analysis of a large pedigree with inherited tubulointerstitial kidney disease.
• Identification of mitochondrial DNA mutations using genetic sequencing.
• Assessment of mitochondrial function in patient-derived fibroblasts, including protein translation and respiration.
• Mitochondrial transfer experiments and in vitro promoter activity assays.

Main Results:

• A homoplasmic substitution (m.547A>T) in the mitochondrial DNA control region was identified in a large pedigree.
• Patient fibroblasts exhibited reduced levels of specific mitochondrial transfer RNAs (tRNAPhe, tRNALeu1), impaired protein translation, and decreased respiration.
• Mitochondrial transfer confirmed the transmission of the defect.
• Reduced heavy strand promoter activity was observed in vitro.
• Identical phenotypes were found in other kindreds with a mutation in mitochondrial tRNAPhe (m.616T>C).

Conclusions:

• Mutations in mitochondrial DNA can cause maternally inherited renal disease.
• The identified mutations likely impair kidney function through reduced activity of mitochondrial tRNAPhe.
• This study demonstrates that mitochondrial DNA control region mutations can be pathogenic, causing specific organ disease without classical mitochondrial symptoms.