Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome

Wu, Shaowen; Li, Lin; Feng, Fan; Wang, Li; Kong, Yuanyuan; Liu, Xiaowei; Yin, Chenghong

doi:10.1186/s13052-021-01112-6

Cited by 5 publications

(4 citation statements)

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“… 21 23 34 In 2021, report of pathogenic compound heterozygous variants in POLR3B in a patient with WRS led to further expansion of the genotypic spectrum of this condition. 23 A prior study has also identified a nonsense variant in POLR3GL , a gene encoding another subunit of RNA polymerase III, as being associated with WRS. 22 …”

Section: Discussionmentioning

confidence: 99%

“…14 15 18 19 In recent years, the phenotypic spectrum of POLR3-related disorders has enlarged significantly, including severe neonatal and infantile presentations to late onset mild ones. [20][21][22][23][24][25][26][27][28][29][30][31][32] Reports of craniofacial characteristics of individuals with POLR3-related disorders are scarce and include patients with biallelic pathogenic variants in POLR1C, 14 a gene also associated with Treacher Collins syndrome (TCS), as well as patients with Wiedemann-Rautenstrauch syndrome (WRS) associated with biallelic pathogenic variants in POLR3A. 21 However, to this day, there have been no studies specifically dedicated to exploring the craniofacial features in POLR3-HLD.…”

Section: Neurogeneticsmentioning

confidence: 99%

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Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants inPOLR3A,POLR3BandPOLR1C

et al. 2023

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BackgroundRNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants inPOLR3A,POLR3B,POLR1CorPOLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants inPOLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants inPOLR3A,POLR3BandPOLR1Care described.MethodsThe craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype–phenotype associations were evaluated.ResultsVarious craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients withPOLR3Bbiallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants inPOLR3AandPOLR3Bwhile a higher proportion of patients withPOLR1Cbiallelic variants demonstrated bitemporal narrowing.ConclusionThrough this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants inPOLR3A,POLR3BandPOLR1C.

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Section: Discussionmentioning

confidence: 99%

Section: Neurogeneticsmentioning

confidence: 99%

Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants inPOLR3A,POLR3BandPOLR1C

et al. 2023

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“…Interestingly, several different syndromes relating to mutations in RNA pol III subunits show very heterogeneous phenotypes. This includes POLR3 -related hypomyelinating leukodystrophies ( Lata et al, 2021 ; Yeganeh and Hernandez, 2020 ; Thomas and Thomas, 2019 ), Wiedemann-Rautenstrauch syndrome, a neonatal progeroid syndrome ( Wu et al, 2021b ; Wambach et al, 2018 ; Paolacci et al, 2017 ; Beauregard-Lacroix et al, 2020 ), and cerebellar hypoplasia with endosteal sclerosis ( Terhal et al, 2020 ; Ghoumid et al, 2017 ). Additionally, Brf1 mutations have been shown to be causative for cerebellofaciodental syndrome ( Borck et al, 2015 ; Jee et al, 2017 ; Honjo et al, 2021 ; Valenzuela et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

MAF1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass

Busschers

Ahmad

Sun

et al. 2022

eLife

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MAF1, a key repressor of RNA polymerase III-mediated transcription, has been shown to promote mesoderm formation in vitro. Here, we show that MAF1 plays a critical role in the regulation of osteoblast differentiation and bone mass. A high bone mass phenotype was noted in mice with a global deletion of Maf1 (Maf1-/- mice). However, osteoblasts isolated from Maf1-/- mice showed reduced osteoblastogenesis ex vivo. Therefore, we determined the effect of MAF1 overexpression specifically in cells from the mesenchymal lineage (Prx1-Cre;LSL-MAF1 mice). These mice showed increased bone mass. Ex vivo, cells from Prx1-Cre;LSL-MAF1 mice showed enhanced osteoblastogenesis concordant with their high bone mass phenotype. Thus, the high bone mass phenotype in Maf1-/- mice is likely due to the confounding effects of the global absence of Maf1 in Maf1-/- mice. MAF1 overexpression promoted osteoblast differentiation and shRNA-mediated Maf1 downregulation inhibited differentiation of ST2 cells, overall indicating MAF1 enhances osteoblast formation. We also found that, in contrast to MAF1 overexpression, other perturbations that repress RNA pol III transcription, including Brf1 knockdown and chemical inhibition of RNA pol III by ML-60218, inhibited osteoblast differentiation. All perturbations that decrease RNA pol III transcription, however, enhanced adipogenesis in ST2 cell cultures. RNA-seq was used to determine the basis for these opposing actions on osteoblast differentiation. The modalities used to perturb RNA pol III transcription resulted in distinct gene expression changes, indicating that this transcription process is highly sensitive and triggers diverse gene expression programs and phenotypic outcomes. Specifically, MAF1 induced genes in ST2 cells known to promote osteoblast differentiation. Furthermore, genes that are induced during osteoblast differentiation displayed codon bias. Together, these results reveal a novel role for MAF1 and RNA pol III-mediated transcription in osteoblast fate determination and differentiation and bone mass regulation.

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“…The POLR3A gene encodes the largest subunit of RNA polymerase III (Pol III), forming the catalytic core with POLR3B. Pol III is responsible for the transcription of different kinds of non-protein-coding RNAs, which regulate transcription, RNA processing, and translation ( Sepehri and Hernandez 1997 ; Werner et al , 2009 ; Wu et al , 2021 ). This protein also acts in the proper function of the nucleolus, including ribosome assembly by enhancing 5S rRNA synthesis and protein translation, determining the metabolic state of the cell ( Tiku and Antebi 2018 ; Báez-Becerra et al , 2020 ).…”

Section: Introductionmentioning

confidence: 99%

DNA repair-related genes and adipogenesis: Lessons from congenital lipodystrophies

et al. 2022

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Classical and progeroid congenital lipodystrophies are a collection of rare diseases displaying a large genetic heterogeneity. They occur due to pathogenic variants in genes associated with adipogenesis, DNA repair pathways, and genome stability. Subjects with lipodystrophy exhibit an impairment in the homeostasis of subcutaneous white adipose tissue (sWAT), resulting in low leptin and adiponectin levels, insulin resistance (IR), diabetes, dyslipidemia, ectopic fat deposition, inflammation, mitochondrial and endoplasmic reticulum commitments, among others. However, how pathogenic variants in adipogenesis-related genes modulate DNA repair in some classical congenital lipodystrophies has not been elucidated. In the same way, no data is clarifying how pathogenic variants in DNA repair genes result in sWAT loss in different types of progeroid lipodystrophies. This review will concentrate on the main molecular findings to understand the link between DNA damage/repair and adipogenesis in human and animal models of congenital lipodystrophies. We will focus on classical and progeroid congenital lipodystrophies directly or indirectly related to DNA repair pathways, highlighting the role of DNA repair-related proteins in maintaining sWAT homeostasis.

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Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome

Cited by 5 publications

References 19 publications

Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants inPOLR3A,POLR3BandPOLR1C

Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants inPOLR3A,POLR3BandPOLR1C

MAF1, a repressor of RNA polymerase III-dependent transcription, regulates bone mass

DNA repair-related genes and adipogenesis: Lessons from congenital lipodystrophies

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