Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism

Hussein Daoud, Martine Tétreault, William Gibson, Kether Guerrero, Ana Cohen, Janina Gburek-Augustat, Matthis Synofzik, Bernard Brais, Cathy A Stevens, Rocio Sanchez-Carpintero, Cyril Goizet, Sakkubai Naidu, Adeline Vanderver, Geneviève Bernard
J Med Genet. 2013-01-25; 50(3): 194-197
DOI: 10.1136/JMEDGENET-2012-101357

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1. J Med Genet. 2013 Mar;50(3):194-7. doi: 10.1136/jmedgenet-2012-101357. Epub 2013
Jan 25.

Mutations in POLR3A and POLR3B are a major cause of hypomyelinating
leukodystrophies with or without dental abnormalities and/or hypogonadotropic
hypogonadism.

Daoud H(1), Tétreault M, Gibson W, Guerrero K, Cohen A, Gburek-Augustat J,
Synofzik M, Brais B, Stevens CA, Sanchez-Carpintero R, Goizet C, Naidu S,
Vanderver A, Bernard G.

Author information:
(1)Center of Excellence in Neuroscience of Université de Montréal, CRCHUM,
Montreal, Quebec, Canada.

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.

DOI: 10.1136/jmedgenet-2012-101357
PMID: 23355746 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus