Defective mitochondrial mrna maturation is associated with spastic ataxia

Andrew H. Crosby; Heema Patel; Barry A. Chioza; Christos Proukakis; Kay Gurtz; Michael A. Patton; Reza Sharifi; Gaurav Harlalka; Michael A. Simpson; Katherine Dick; Johanna A. Reed; Ali Al-Memar; Zofia M.A. Chrzanowska-Lightowlers; Harold E. Cross; Robert N. Lightowlers

doi:10.1016/j.ajhg.2010.09.013

Defective mitochondrial mrna maturation is associated with spastic ataxia

Andrew H. Crosby, Heema Patel, Barry A. Chioza, Christos Proukakis, Kay Gurtz, Michael A. Patton, Reza Sharifi, Gaurav Harlalka, Michael A. Simpson, Katherine Dick, Johanna A. Reed, Ali Al-Memar, Zofia M.A. Chrzanowska-Lightowlers, Harold E. Cross, Robert N. Lightowlers

Ophthalmology and Vision Sciences

Research output: Contribution to journal › Article › peer-review

69 Scopus citations

Abstract

In human mitochondria, polyadenylation of mRNA, undertaken by the nuclear-encoded mitochondrial poly(A) RNA polymerase, is essential for maintaining mitochondrial gene expression. Our molecular investigation of an autosomal-recessive spastic ataxia with optic atrophy, present among the Old Order Amish, identified a mutation of MTPAP associated with the disease phenotype. When subjected to poly(A) tail-length assays, mitochondrial mRNAs from affected individuals were shown to have severely truncated poly(A) tails. Although defective mitochondrial DNA maintenance underlies a well-described group of clinical disorders, our findings reveal a defect of mitochondrial mRNA maturation associated with human disease and imply that this disease mechanism should be considered in other complex neurodegenerative disorders.

Original language	English (US)
Pages (from-to)	655-660
Number of pages	6
Journal	American Journal of Human Genetics
Volume	87
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2010.09.013
State	Published - Nov 12 2010

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Crosby, A. H., Patel, H., Chioza, B. A., Proukakis, C., Gurtz, K., Patton, M. A., Sharifi, R., Harlalka, G., Simpson, M. A., Dick, K., Reed, J. A., Al-Memar, A., Chrzanowska-Lightowlers, Z. M. A., Cross, H. E., & Lightowlers, R. N. (2010). Defective mitochondrial mrna maturation is associated with spastic ataxia. American Journal of Human Genetics, 87(5), 655-660. https://doi.org/10.1016/j.ajhg.2010.09.013

Crosby, AH, Patel, H, Chioza, BA, Proukakis, C, Gurtz, K, Patton, MA, Sharifi, R, Harlalka, G, Simpson, MA, Dick, K, Reed, JA, Al-Memar, A, Chrzanowska-Lightowlers, ZMA, Cross, HE & Lightowlers, RN 2010, 'Defective mitochondrial mrna maturation is associated with spastic ataxia', American Journal of Human Genetics, vol. 87, no. 5, pp. 655-660. https://doi.org/10.1016/j.ajhg.2010.09.013

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abstract = "In human mitochondria, polyadenylation of mRNA, undertaken by the nuclear-encoded mitochondrial poly(A) RNA polymerase, is essential for maintaining mitochondrial gene expression. Our molecular investigation of an autosomal-recessive spastic ataxia with optic atrophy, present among the Old Order Amish, identified a mutation of MTPAP associated with the disease phenotype. When subjected to poly(A) tail-length assays, mitochondrial mRNAs from affected individuals were shown to have severely truncated poly(A) tails. Although defective mitochondrial DNA maintenance underlies a well-described group of clinical disorders, our findings reveal a defect of mitochondrial mRNA maturation associated with human disease and imply that this disease mechanism should be considered in other complex neurodegenerative disorders.",

author = "Crosby, {Andrew H.} and Heema Patel and Chioza, {Barry A.} and Christos Proukakis and Kay Gurtz and Patton, {Michael A.} and Reza Sharifi and Gaurav Harlalka and Simpson, {Michael A.} and Katherine Dick and Reed, {Johanna A.} and Ali Al-Memar and Chrzanowska-Lightowlers, {Zofia M.A.} and Cross, {Harold E.} and Lightowlers, {Robert N.}",

note = "Funding Information: This work was supported by the Birth Defects Foundation (UK)/Newlife Foundation for Disabled Children. We would like to thank the Amish families for participating in this study. Sequencing was done in the Medical Biomics (St. George's, University of London). R.N.L. and Z.M.A.C.-L. would like to thank The Wellcome Trust (074454/Z/04/Z) and the Biotechnology and Biological Sciences Research Council (BB/F011520/1) for continuing support. ",

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AU - Crosby, Andrew H.

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AU - Gurtz, Kay

AU - Patton, Michael A.

AU - Sharifi, Reza

AU - Harlalka, Gaurav

AU - Simpson, Michael A.

AU - Dick, Katherine

AU - Reed, Johanna A.

AU - Al-Memar, Ali

AU - Chrzanowska-Lightowlers, Zofia M.A.

AU - Cross, Harold E.

AU - Lightowlers, Robert N.

N1 - Funding Information: This work was supported by the Birth Defects Foundation (UK)/Newlife Foundation for Disabled Children. We would like to thank the Amish families for participating in this study. Sequencing was done in the Medical Biomics (St. George's, University of London). R.N.L. and Z.M.A.C.-L. would like to thank The Wellcome Trust (074454/Z/04/Z) and the Biotechnology and Biological Sciences Research Council (BB/F011520/1) for continuing support.

PY - 2010/11/12

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N2 - In human mitochondria, polyadenylation of mRNA, undertaken by the nuclear-encoded mitochondrial poly(A) RNA polymerase, is essential for maintaining mitochondrial gene expression. Our molecular investigation of an autosomal-recessive spastic ataxia with optic atrophy, present among the Old Order Amish, identified a mutation of MTPAP associated with the disease phenotype. When subjected to poly(A) tail-length assays, mitochondrial mRNAs from affected individuals were shown to have severely truncated poly(A) tails. Although defective mitochondrial DNA maintenance underlies a well-described group of clinical disorders, our findings reveal a defect of mitochondrial mRNA maturation associated with human disease and imply that this disease mechanism should be considered in other complex neurodegenerative disorders.

AB - In human mitochondria, polyadenylation of mRNA, undertaken by the nuclear-encoded mitochondrial poly(A) RNA polymerase, is essential for maintaining mitochondrial gene expression. Our molecular investigation of an autosomal-recessive spastic ataxia with optic atrophy, present among the Old Order Amish, identified a mutation of MTPAP associated with the disease phenotype. When subjected to poly(A) tail-length assays, mitochondrial mRNAs from affected individuals were shown to have severely truncated poly(A) tails. Although defective mitochondrial DNA maintenance underlies a well-described group of clinical disorders, our findings reveal a defect of mitochondrial mRNA maturation associated with human disease and imply that this disease mechanism should be considered in other complex neurodegenerative disorders.

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Defective mitochondrial mrna maturation is associated with spastic ataxia

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