Leukodystrophy, Hypomyelinating, 11

A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-11 (HLD11) is caused by homozygous or compound heterozygous mutation in the POLR1C gene (610060) on chromosome 6p21.

Description

Hypomyelinating leukodystrophy-11 is an autosomal recessive neurologic disorder characterized by delayed psychomotor development and other neurologic features associated with hypomyelination on brain imaging. Some patients may have additional nonneurologic features, particularly dental abnormalities and possibly hypogonadotropic hypogonadism (summary by Thiffault et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

Clinical Features

Thiffault et al. (2015) reported 8 unrelated patients with hypomyelinating leukodystrophy. All had neurologic abnormalities, including delayed psychomotor development, loss or lack of independent ambulation, abnormal cognition, tremor, ataxia, spasticity, and cerebellar findings. Three had myopia and 3 had dental abnormalities. Six patients were too young to be assessed for hypogonadotropic hypogonadism, and 2 did not have hypogonadism. Brain imaging showed hypomyelination and thin corpus callosum in all patients, with cerebellar atrophy in 5 patients.

Inheritance

The transmission pattern of HLD11 in the families reported by Thiffault et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 patients with HLD11 who were negative for mutations in the POLR3A (614258) and POLR3B (614366) genes, Thiffault et al. (2015) identified 13 homozygous or compound heterozygous mutations in the POLR1C gene (see, e.g., 610060.0006-610060.0011). Mutations in the first 3 patients were found by whole-exome sequencing and segregated with the disorder in the families; subsequent mutations were found by direct sequencing of the POLR1C gene in 16 individuals with a similar phenotype who were negative for POLR3A and POLR3B mutations. In vitro functional expression studies of 2 of the mutations (N74S; 610060.0006 and N32I; 610060.0007) in HeLa cells showed that the mutant proteins interacted less well with POLR3 than did wildtype, suggesting a selective defect in POLR3 assembly that did not affect POLR1 assembly. Immunofluorescence and immunoprecipitation studies showed cytoplasmic accumulation of mutated POLR1C subunits and reduced binding to POLR3-transcribed genes. In contrast, there was no difference between mutant and wildtype POLR1C in binding to POLR1-transcribed genes. The findings indicated that these mutations specifically interfered with assembly, nuclear import, and chromatin association of POLR3.