A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay.
Autosomal-recessive cerebellar atrophy is usually associated with inactivating mutations and early-onset presentation. The underlying molecular diagnosis suggests the involvement of neuronal survival pathways, but many mechanisms are still lacking and most patients elude genetic diagnosis. Using whole exome sequencing, we identified homozygous p.Val55Ala in the THG1L (tRNA-histidine guanylyltransferase 1 like) gene in three siblings who presented with cerebellar signs, developmental delay, dysarthria, and pyramidal signs and had cerebellar atrophy on brain MRI. THG1L protein was previously reported to participate in mitochondrial fusion via its interaction with MFN2. Abnormal mitochondrial fragmentation, including mitochondria accumulation around the nuclei and confinement of the mitochondrial network to the nuclear vicinity, was observed when patient fibroblasts were cultured in galactose containing medium. Culturing cells in galactose containing media promotes cellular respiration by oxidative phosphorylation and the action of the electron transport chain thus stimulating mitochondrial activity. The growth defect of the yeast thg1Δ strain was rescued by the expression of either yeast Thg1 or human THG1L; however, clear growth defect was observed following the expression of the human p.Val55Ala THG1L or the corresponding yeast mutant. A defect in the protein tRNAHisguanylyltransferase activity was excluded by the normal in vitro G-1addition to either yeast tRNAHisor human mitochondrial tRNAHisin the presence of the THG1L mutation. We propose that homozygosity for the p.Val55Ala mutation in THG1L is the cause of the abnormal mitochondrial network in the patient fibroblasts, likely by interfering with THG1L activity towards MFN2. This may result in lack of mitochondria in the cerebellar Purkinje dendrites, with degeneration of Purkinje cell bodies and apoptosis of granule cells, as reported for MFN2 deficient mice.
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.|Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Simon
S
Edvardson
Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA, 95616, USA.
Yael
Y
Elbaz-Alon
Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY, USA.
Chaim
C
Jalas
Department of Chemistry and Biochemistry, Ohio State Biochemistry Program and Center for RNA Biology, The Ohio State University, Columbus, OH, USA.
Ashanti
A
Matlock
Department of Chemistry and Biochemistry, Ohio State Biochemistry Program and Center for RNA Biology, The Ohio State University, Columbus, OH, USA.
Krishna
K
Patel
Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA, 95616, USA.
Katherine
K
Labbé
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Avraham
A
Shaag
Department of Chemistry and Biochemistry, Ohio State Biochemistry Program and Center for RNA Biology, The Ohio State University, Columbus, OH, USA. jackman.14@osu.edu.
Jane E
JE
Jackman
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Elpeleg@hadassah.org.il.
Orly
O
Elpeleg
D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002524:Cerebellar Ataxia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D002658:Developmental Disabilities / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D005260:Female; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D063154:Mitochondrial Dynamics; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D035781:Siblings
D011506:Proteins; C532028:THG1L protein, human
Cerebellar atrophy; Mitochondrial disorders; Mitochondrial fusion