Defective mitochondrial mRNA maturation is associated with spastic ataxia.
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.
Centre for Medical Genetics, St. George's University London, UK. acrosby@sgul.ac.uk
Andrew H
AH
Crosby
Heema
H
Patel
Barry A
BA
Chioza
Christos
C
Proukakis
Kay
K
Gurtz
Michael A
MA
Patton
Reza
R
Sharifi
Gaurav
G
Harlalka
Michael A
MA
Simpson
Katherine
K
Dick
Johanna A
JA
Reed
Ali
A
Al-Memar
Zofia M A
ZM
Chrzanowska-Lightowlers
Harold E
HE
Cross
Robert N
RN
Lightowlers
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D005260:Female; D050259:Genes, Mitochondrial; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009896:Optic Atrophy / Q000235:genetics; D020336:Paraparesis, Spastic / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial
D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D000077278:RNA, Mitochondrial; C029305:mitochondrial messenger RNA; D012321:DNA-Directed RNA Polymerases; C555258:MTPAP protein, human