Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.
BACKGROUND
Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterised by abnormal central nervous system white matter. Mutations in POLR3A and POLR3B genes were recently reported to cause four clinically overlapping hypomyelinating leukodystrophy phenotypes. Our aim was to investigate the presence and frequency of POLR3A and POLR3B mutations in patients with genetically unexplained hypomyelinating leukodystrophies with typical clinical and/or radiologic features of Pol III-related leukodystrophies.


METHODS
The entire coding region and the flanking exon/intron boundaries of POLR3A and/or POLR3B genes were amplified and sequenced in 14 patients.


RESULTS
Recessive mutations in POLR3A or POLR3B were uncovered in all 14 patients. Eight novel mutations were identified in POLR3A: six missenses, one nonsense, and one frameshift mutation. Seven patients carried compound heterozygous mutations in POLR3B, of whom six shared the common mutation in exon 15 (p.V523E). Seven novel mutations were identified in POLR3B: four missenses, two splice sites, and one intronic mutation.


CONCLUSIONS
To date, our group has described 37 patients, of whom 27 have mutations in POLR3A and 10 in POLR3B, respectively. Altogether, our results further support the proposal that POLR3A and POLR3B mutations are a major cause of hypomyelinating leukodystrophies and suggest that POLR3A mutations are more frequent.
Center of Excellence in Neuroscience of Université de Montréal, CRCHUM, Montreal, Quebec, Canada.
Hussein
H
Daoud
Martine
M
Tétreault
William
W
Gibson
Kether
K
Guerrero
Ana
A
Cohen
Janina
J
Gburek-Augustat
Matthis
M
Synofzik
Bernard
B
Brais
Cathy A
CA
Stevens
Rocio
R
Sanchez-Carpintero
Cyril
C
Goizet
Sakkubai
S
Naidu
Adeline
A
Vanderver
Geneviève
G
Bernard
D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D012320:RNA Polymerase III / Q000235:genetics*; D014071:Tooth Abnormalities / Q000235:genetics*
C468558:POLR3B protein, human; D012320:RNA Polymerase III