BRF1 mutations in a family with growth failure, markedly delayed bone age, and central nervous system anomalies

Abstract

Linear growth failure can be caused by many different genetic abnormalities. In many cases, the genetic defect affects not only the growth plate, causing short stature, but also other organs/tissues causing additional clinical abnormalities. The proband was evaluated at 10 years of age for impaired postnatal linear growth (height 113.3 cm, −4.6 SDS), a bone age that was delayed by 5 years, dysmorphic facies, cognitive impairment, and central nervous system anomalies. His younger brother, presented only with growth failure at 10 months of age. Exome sequencing identified compound heterozygous variants in the gene encoding RNA polymerase III transcription initiation factor 90 kDa subunit (BRF1) in both affected siblings: a missense mutation (c.875 C>G:p.P292R) and a frameshift mutation (c.551delG:p.C184Sfs). The frameshift mutation is expected to lead to nonsense-mediated mRNA decay (NMD) and/or to protein truncation. Expression of BRF1 with the P292R missense mutation failed to rescue yeast lacking BRF1. The findings confirm a previous report showing that biallelic mutations in BRF1 cause cerebellar-facial-dental syndrome. Our findings also help define the growth phenotype, indicating that the linear growth failure can become clinically evident before the neurological abnormalities and that a severely delayed bone age may serve as a diagnostic clue.

QRICH1 mutations cause a chondrodysplasia with developmental delay

“…Single nucleotide polymorphism (SNP) array was performed by the Cancer Genetics and Comparative Genomics Branch at National Human Genome Research Institute (NHGRI) using the Infinium HumanOmniExpressExome DNA analysis kit (Illumina, San Diego, CA) according to the manufacturer's instruction. Exome sequencing was performed by the NIH Intramural Sequencing Center (NISC) as previously described . Methods for plasmid preparation, site‐directed mutagenesis, western blot, chondrocyte isolation and transfection, 3 H‐thymidine uptake, RNA extraction and purification, quantitative RT‐PCR, and whole‐mount embryo in situ hybridization are provided in the Supporting Information.…”

Maf1 and Repression of RNA Polymerase III-Mediated Transcription Drive Adipocyte Differentiation

“…Mutations in RNA pol III subunits are associated with a variety of human developmental diseases, including leukodystrophy ( Daoud et al, 2013 ; Thiffault et al, 2015 ) and Treacher Collins syndrome ( Dauwerse et al, 2011 ). Mutations in BRF1 , encoding a TFIIIB transcription factor subunit, were shown to be causal for human cerebellar-facial-dental syndrome ( Borck et al, 2015 ; Jee et al, 2017 ), whereas mutation in BDP1 , another TFIIIB subunit, was associated with hereditary hearing loss ( Girotto et al, 2013 ). Several studies have further indicated a role for RNA pol III in cellular differentiation and development.…”

“…In contrast to what is known about the function of Maf1 in repressing oncogenesis, little is known about its potential role in other biological processes. Emerging studies are revealing that mutations in RNA pol III and its transcription components are associated with various human disorders ( Borck et al, 2015 ; Daoud et al, 2013 ; Dauwerse et al, 2011 ; Girotto et al, 2013 ; Jee et al, 2017 ; Thiffault et al, 2015 ), yet how this transcription process or Maf1 might regulate developmental programs and cell fate determination is not yet known. We therefore examined a potential role for Maf1 in early development and cellular differentiation by using embryonic stem cells (ESCs).…”

RNA polymerase III transcription as a disease factor

“…Heterozygous BRF1 mutations, including a frameshift and a missense mutation (p.P292R) that affects the same amino acid (p.P292) as one of the mutations (p.P292H) described by Borck et al (2015) (Jee et al 2017), were also uncovered in another family with growth failure and central nervous system anomalies. The P292H as well as a P292R mutations were further shown to prevent yeast growth when introduced into yeast Brf1 (Jee et al 2017), again consistent with decreased BRF1 activity causing or contributing to the disorder.…”