POLR3B-associated leukodystrophy: clinical, neuroimaging and molecular-genetic analyses in four patients: clinical heterogeneity and novel mutations in POLR3B gene.
A definite molecular diagnosis was obtained in 5/10 families and included the following diseases: autosomal recessive spastic ataxia of Charlevoix-Saguenay, POLR3B-related hypomyelinating leukodystrophy, primary coenzyme Q10 deficiency type 4, Niemann-Pick disease type C1 and SYNE1-related ataxia.
To determine if other POLR3-HLD mutations can cause a leukodystrophy phenotype in mouse, we characterized mice carrying the Polr3b mutation c.308G > A (p.Arg103His).
POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy.
Recessive Mutations in POLR3B Encoding RNA Polymerase III Subunit Causing Diffuse Hypomyelination in Patients with 4H Leukodystrophy with Polymicrogyria and Cataracts.
Variants in three other RNA polymerase subunits, POLR1C, POLR3A and POLR3B, are known to cause recessive leukodystrophy similar to the disease afflicting the present family but with a later onset.
POLR3-related leukodystrophy is diagnosed by the combination of classic clinical findings, typical brain MRI features, and the presence of biallelic pathogenic variants in <i>POLR3A</i>, <i>POLR3B,</i> or <i>POLR1C</i>.
This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are associated with 4H leukodystrophy, in a cohort of patients with unclassified hypomyelination.
The classical form is characterized by the association of hypomyelination, abnormal dentition, and hypogonadotropic hypogonadism, but the recent identification of two genes (POLR3A and POLR3B) responsible for the syndrome demonstrates that these three main characteristics can be variably combined among "Pol-III (polymerase III)-related leukodystrophies."
A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B.
The objectives of this study are (1) to define the neuroradiologic pattern in a cohort of POLR3A and POLR3B subjects and (2) to compare the neuroradiologic pattern of Pol III-related leukodystrophies with other hypomyelinating disorders.
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.