title: A novel in-frame 18-bp microdeletion in MT-CYB causes a multisystem disorder with prominent exercise intolerance.
abstract: 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.
authors.affiliation: Dipartimento di Biologia e Biotecnologie "L. Spallanzani", Università di Pavia, Pavia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Carossa
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Concetta Valentina
authors.initials: CV
authors.lastname: Tropeano
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maresca
authors.forename: Leonardo
authors.initials: L
authors.lastname: Caporali
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.forename: Michele
authors.initials: M
authors.lastname: Carbonelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Caterina
authors.initials: C
authors.lastname: Tonon
authors.forename: Raffaele
authors.initials: R
authors.lastname: Lodi
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Vera
authors.initials: V
authors.lastname: De Nardo
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Luca
authors.initials: L
authors.lastname: Ferretti
authors.forename: Francesca
authors.initials: F
authors.lastname: Gandini
authors.forename: Maria
authors.initials: M
authors.lastname: Pala
authors.forename: Alessandro
authors.initials: A
authors.lastname: Achilli
authors.forename: Anna
authors.initials: A
authors.lastname: Olivieri
authors.forename: Antonio
authors.initials: A
authors.lastname: Torroni
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000328:Adult; D001483:Base Sequence; D002386:Cataract / Q000235:genetics / Q000473:pathology; D045303:Cytochromes b / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D003680:Deglutition Disorders / Q000235:genetics / Q000473:pathology; D005221:Fatigue / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D010857:Pigment Epithelium of Eye / Q000473:pathology; D017384:Sequence Deletion; D014075:Tooth Discoloration / Q000235:genetics / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D045303:Cytochromes b
keywords: MT-CYB; cybrid; exercise intolerance; mtDNA; multi system mitochondrial disease