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.
Crosby
Andrew H
AH
Centre for Medical Genetics, St. George's University London, UK. acrosby@sgul.ac.uk
Patel
Heema
H
Chioza
Barry A
BA
Proukakis
Christos
C
Gurtz
Kay
K
Patton
Michael A
MA
Sharifi
Reza
R
Harlalka
Gaurav
G
Simpson
Michael A
MA
Dick
Katherine
K
Reed
Johanna A
JA
Al-Memar
Ali
A
Chrzanowska-Lightowlers
Zofia M A
ZM
Cross
Harold E
HE
Lightowlers
Robert N
RN
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