Identification of a Novel Missense Mutation of POLR3A Gene in a Cohort of Sicilian Patients with Leukodystrophy

Antonino Musumeci; Francesco Calì; Carmela Scuderi; Mirella Vinci; Girolamo Aurelio Vitello; Sebastiano Antonino Musumeci; Valeria Chiavetta; Concetta Federico; Greta Amore; Salvatore Saccone; Gabriella Di Rosa; Antonio Gennaro Nicotera

doi:10.3390/biomedicines10092276

Identification of a Novel Missense Mutation of POLR3A Gene in a Cohort of Sicilian Patients with Leukodystrophy

Biomedicines. 2022 Sep 14;10(9):2276. doi: 10.3390/biomedicines10092276.

Affiliations

¹ Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy.
² Department Biological, Geological and Environmental Sciences, University of Catania, Via Androne 81, 95124 Catania, Italy.
³ Department of Human Pathology of the Adult and Developmental Age, "Gaetano Barresi" University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy.

Abstract

Recessive mutations in the POLR3A gene cause POLR3-HLD (the second-most-common form of childhood-onset hypomyelinating leukodystrophy), a neurodegenerative disorder featuring deficient cerebral myelin formation. To date, more than 140 POLR3A (NM_007055.3) missense mutations are related to the pathogenesis of POLR3-related leukodystrophy and spastic ataxia. Herein, in a cohort of five families from Sicily (Italy), we detected two cases of patients affected by POLR3-related leukodystrophy, one due to a compound heterozygous mutation in the POLR3A gene, including a previously undescribed missense mutation (c.328A > G (p.Lys110Glu)). Our study used an in-house NGS gene panel comprising 41 known leukodystrophy genes. Successively, we used a predictive test supporting the missense mutation as causative of disease, thus this mutation can be considered “Likely Pathogenic” and could be as a new pathogenetic mutation of the POLR3A gene causing a severe form of POLR3-HLD.

Keywords: POLR3A; hypomyelination; leukodystrophy; missense mutation; neurodegenerative disorder.

Grants and funding

This work has been partially supported by the Italian Ministry of Health—“Ricerca Corrente” and 5 × mille, and by Research Plan PIACERI L.3 Starting Grant from Dept. B.G.E.S., University of Catania, to C.F.