TY - JOUR
T1 - Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease
AU - Indrieri, Alessia
AU - Van Rahden, Vanessa Alexandra
AU - Tiranti, Valeria
AU - Morleo, Manuela
AU - Iaconis, Daniela
AU - Tammaro, Roberta
AU - D'Amato, Ilaria
AU - Conte, Ivan
AU - Maystadt, Isabelle
AU - Demuth, Stephanie
AU - Zvulunov, Alex
AU - Kutsche, Kerstin
AU - Zeviani, Massimo
AU - Franco, Brunella
N1 - Funding Information:
This work was supported by the Pierfranco and Luisa Mariani Foundation Italy, the Italian Telethon Foundation (GGP11011 and GPP10005), CARIPLO grant 2011/0526, and the Italian Association of Mitochondrial Disease Patients and Families (Mitocon) (to M.Z.) and the Deutsche Forschungsgemeinschaft (KU 1240/6-1 to K.K.). B.F. is also supported by the Italian Telethon Foundation. We thank Sandro Banfi, Nicola Brunetti-Pierri, and Graciana Diez-Roux for critical reading of the manuscript and helpful discussion. We also thank Francesco Salierno and Inka Jantke for excellent technical assistance.
PY - 2012/11/2
Y1 - 2012/11/2
N2 - Microphthalmia with linear skin lesions (MLS) is an X-linked dominant male-lethal disorder associated with mutations in holocytochrome c-type synthase (HCCS), which encodes a crucial player of the mitochondrial respiratory chain (MRC). Unlike other mitochondrial diseases, MLS is characterized by a well-recognizable neurodevelopmental phenotype. Interestingly, not all clinically diagnosed MLS cases have mutations in HCCS, thus suggesting genetic heterogeneity for this disorder. Among the possible candidates, we analyzed the X-linked COX7B and found deleterious de novo mutations in two simplex cases and a nonsense mutation, which segregates with the disease, in a familial case. COX7B encodes a poorly characterized structural subunit of cytochrome c oxidase (COX), the MRC complex IV. We demonstrated that COX7B is indispensable for COX assembly, COX activity, and mitochondrial respiration. Downregulation of the COX7B ortholog (cox7B) in medaka (Oryzias latipes) resulted in microcephaly and microphthalmia that recapitulated the MLS phenotype and demonstrated an essential function of complex IV activity in vertebrate CNS development. Our results indicate an evolutionary conserved role of the MRC complexes III and IV for the proper development of the CNS in vertebrates and uncover a group of mitochondrial diseases hallmarked by a developmental phenotype.
AB - Microphthalmia with linear skin lesions (MLS) is an X-linked dominant male-lethal disorder associated with mutations in holocytochrome c-type synthase (HCCS), which encodes a crucial player of the mitochondrial respiratory chain (MRC). Unlike other mitochondrial diseases, MLS is characterized by a well-recognizable neurodevelopmental phenotype. Interestingly, not all clinically diagnosed MLS cases have mutations in HCCS, thus suggesting genetic heterogeneity for this disorder. Among the possible candidates, we analyzed the X-linked COX7B and found deleterious de novo mutations in two simplex cases and a nonsense mutation, which segregates with the disease, in a familial case. COX7B encodes a poorly characterized structural subunit of cytochrome c oxidase (COX), the MRC complex IV. We demonstrated that COX7B is indispensable for COX assembly, COX activity, and mitochondrial respiration. Downregulation of the COX7B ortholog (cox7B) in medaka (Oryzias latipes) resulted in microcephaly and microphthalmia that recapitulated the MLS phenotype and demonstrated an essential function of complex IV activity in vertebrate CNS development. Our results indicate an evolutionary conserved role of the MRC complexes III and IV for the proper development of the CNS in vertebrates and uncover a group of mitochondrial diseases hallmarked by a developmental phenotype.
UR - http://www.scopus.com/inward/record.url?scp=84868366941&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.09.016
DO - 10.1016/j.ajhg.2012.09.016
M3 - Article
AN - SCOPUS:84868366941
SN - 0002-9297
VL - 91
SP - 942
EP - 949
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -