A novel in-frame 18-bp microdeletion in MT-CYB causes a multisystem disorder with prominent exercise intolerance

Hum Mutat. 2014 Aug;35(8):954-8. doi: 10.1002/humu.22596. Epub 2014 Jun 28.


A novel heteroplasmic mitochondrial DNA (mtDNA) microdeletion affecting the cytochrome b gene (MT-CYB) was identified in an Italian female patient with a multisystem disease characterized by sensorineural deafness, cataracts, retinal pigmentary dystrophy, dysphagia, postural and gait instability, and myopathy with prominent exercise intolerance. The deletion is 18-base pair long and encompasses nucleotide positions 15,649-15,666, causing the loss of six amino acids (Ile-Leu-Ala-Met-Ile-Pro) in the protein, but leaving the remaining of the MT-CYB sequence in frame. The defective complex III function was cotransferred with mutant mtDNA in cybrids, thus unequivocally establishing its pathogenic role. Maternal relatives failed to show detectable levels of the deletion in blood and urinary epithelium, suggesting a de novo mutational event. This is the second report of an in-frame intragenic deletion in MT-CYB, which most likely occurred in early stages of embryonic development, associated with a severe multisystem disorder with prominent exercise intolerance.

Keywords: MT-CYB; cybrid; exercise intolerance; mtDNA; multi system mitochondrial disease.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence*
  • Cataract / genetics
  • Cataract / pathology
  • Cytochromes b / genetics*
  • DNA, Mitochondrial / genetics
  • Deglutition Disorders / genetics
  • Deglutition Disorders / pathology
  • Fatigue / genetics*
  • Fatigue / pathology
  • Female
  • Gene Expression
  • Hearing Loss, Sensorineural / genetics
  • Hearing Loss, Sensorineural / pathology
  • Humans
  • Molecular Sequence Data
  • Muscular Diseases / genetics*
  • Muscular Diseases / pathology
  • Pigment Epithelium of Eye / pathology
  • Sequence Deletion*
  • Tooth Discoloration / genetics
  • Tooth Discoloration / pathology


  • DNA, Mitochondrial
  • Cytochromes b

Supplementary concepts

  • Sensorineural Hearing Loss, Retinal Pigment Epithelium Lesions, Discolored Teeth