A variant of neonatal progeroid syndrome, or Wiedemann–Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL

Beauregard‐Lacroix, Éliane; Salian, Smrithi; Kim, Hyunyun; Ehresmann, Sophie; DʹAmours, Guylaine; Gauthier, Julie; Saillour, Virginie; Bernard, Geneviève; Mitchell, Grant A.; Soucy, Jean‐François; Michaud, Jacques L.; Campeau, Philippe M.

doi:10.1038/s41431-019-0539-6

Cited by 20 publications

(18 citation statements)

References 27 publications

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“…Therefore, the phenotype is clinically not regarded as Wiedemann‐Rautenstrauch syndrome. Exome sequencing detected a homozygous loss‐of‐function mutation in POLR3GL , which is also coding for a subunit of DNA‐dependent RNA polymerase III 155 . In addition, biallelic POLR3GL mutations leading to aberrant splicing were described in three patients with endosteal hyperostosis, oligodontia, short stature and mild facial dysmorphism 156 …”

Section: Pathogenesis and Clinical Phenotypes Of Selected Premature Amentioning

confidence: 99%

Premature aging disorders: A clinical and genetic compendium

2020

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Progeroid disorders make up a heterogeneous group of very rare hereditary diseases characterized by clinical signs that often mimic physiological aging in a premature manner. Apart from Hutchinson-Gilford progeria syndrome, one of the bestinvestigated progeroid disorders, a wide spectrum of other premature aging phenotypes exist, which differ significantly in their clinical presentation and molecular pathogenesis. Next-generation sequencing (NGS)-based approaches have made it feasible to determine the molecular diagnosis in the early stages of a disease. Nevertheless, a broad clinical knowledge on these disorders and their associated symptoms is still fundamental for a comprehensive patient management and for the interpretation of variants of unknown significance from NGS data sets. This review provides a detailed overview on characteristic clinical features and underlying molecular genetics of well-known as well as only recently identified premature aging disorders and also highlights novel findings towards future therapeutic options. K E Y W O R D S characteristic clinical features, hereditary, premature aging, progeroid disorders 1 | INTRODUCTION Aging is a general biological phenomenon that affects all human beings and results in a functional decline of physiological systems accompanied by an increased risk for chronic ailments with advancing chronological age. 1,2 At the molecular level, aging is for example associated with genomic instability, loss of heterochromatin, and the accumulation of macromolecular damage leading to reduced (stem) cell function and tissue regeneration. 3 Progeroid disorders show many clinical features of aging-associated pathologies and signs similar to physiological aging; however, they occur at earlier ages and often progress rapidly. In many aspects progeria therefore represents a timelapse form of aging. Premature aging processes are mostly segmental in that they involve one or more organs, but do not exhibit all aspects associated with physiological aging. Premature aging signs include, among others, alopecia, hair graying, lipodystrophy, osteoporosis, joint contractures, cataract, hearing loss, atherosclerosis, cardiovascular diseases, diabetes mellitus and malignancies at an early age. In addition to these typical aging phenotypes, progeria patients may also present with growth retardation, developmental delay, and intellectual disability. A more modular view of segmental premature aging syndromes hypothesizes that a cluster of symptoms appearing in several disorders might be due to a common underlying cause-for example, alopecia, osteoporosis and nail atrophy have been proposed to be related to telomere shortening. 4 Research into premature aging disorders aims at understanding the pathogenesis and to develop novel treatment strategies, but also intends to unshadow physiological aging processes since premature aging phenotypes mirror many of the clinical aspects of physiological aging. 3 One of the best-known premature aging disorders is the Hutchinson-Gilford progeria syndr...

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Section: Pathogenesis and Clinical Phenotypes Of Selected Premature Amentioning

confidence: 99%

Premature aging disorders: A clinical and genetic compendium

2020

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“…Based on the genetic variants and the clinical phenotype of the patient, we believe that the patient should be diagnosed with WRS. The genes associated with WRS pathogenesis, identified in previous studies, are POLR3A and POLR3GL [ 6 , 9 ]. Therefore, POLR3B identified in the present study is a novel pathogenic gene for WRS.…”

Section: Discussionmentioning

confidence: 99%

“…However, we did not find any potential pathogenic variants of LMNA in the proband. We also focused on the pathogenic genes of other diseases related to progeria, such as POLR3A [ 5 , 6 ] and POLR3GL [ 9 ], and we only found a heterozygous POLR3A variant, c.1771-6C > A, which is an intron variant, in the WES data. Since the biallelic mutations of POLR3A were pathogenic, the heterozygous intron variant that we found may not be related to the occurrence of the disease.…”

Section: Case Presentationmentioning

confidence: 99%

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

Feng

et al. 2021

Ital J Pediatr

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Background Wiedemann-Rautenstrauch syndrome (WRS) is a rare autosomal recessive neonatal progeroid disorder characterized by prenatal and postnatal growth retardation, short stature, a progeroid appearance, hypotonia, and mental impairment. Case presentation A 6-year-old patient, who initially presented with multiple postnatal abnormalities, facial dysplasia, micrognathia, skull appearance, hallux valgus, and congenital dislocation of the hip, was recruited in this study. The patient was initially diagnosed with progeria. The mother of the patient had abnormal fetal development during her second pregnancy check-up, and the clinical phenotype of the fetus was similar to that of the patient. Whole-exome sequencing (WES) of the patient was performed, and POLR3B compound heterozygous variants—c.2191G > C:p.E731Q and c.3046G > A:p.V1016M—were identified in the patient. Using Sanger sequencing, we found that the phenotypes and genotypes were segregated within the pedigree. These two variants are novel and not found in the gnomAD and 1000 Genomes databases. The two mutation sites are highly conserved between humans and zebrafish. Conclusions Our study not only identified a novel WRS-associated gene, POLR3B, but also broadened the mutational and phenotypic spectra of POLR3B. Furthermore, WES may be useful for identifying rare disease-related genetic variants.

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“…As the disease spectrum widens 11 – 17 , with hypomyelination not always present, and mutations in POLR3 genes being found to explain other previously described disorders, they are collectively increasingly referred to as POLR3-related disorders 11 – 13 , 18 – 22 . With this new definition, one other POLR3 gene, POLR3GL , was added to the list of genes with biallelic mutations causing disorders with overlapping manifestations but without a leukodystrophy 23 , 24 . POLR3GL is an interesting Pol III subunit as it is homologous to POLR3G.…”

mentioning

confidence: 99%

POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?

Coulombe¹,

Derksen²,

Piana³

et al. 2021

Fac Rev

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Hypomyelinating leukodystrophies are a group of genetic disorders characterized by insufficient myelin deposition during development. A subset of hypomyelinating leukodystrophies, named RNA polymerase III (Pol III or POLR3)-related leukodystrophy or 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) leukodystrophy, was found to be caused by biallelic variants in genes encoding subunits of the enzyme Pol III, including POLR3A, POLR3B, POLR3K, and POLR1C. Pol III is one of the three nuclear RNA polymerases that synthesizes small non-coding RNAs, such as tRNAs, 5S RNA, and others, that are involved in the regulation of essential cellular processes, including transcription, translation and RNA maturation. Affinity purification coupled with mass spectrometry (AP-MS) revealed that a number of mutations causing POLR3-related leukodystrophy impair normal assembly or biogenesis of Pol III, often causing a retention of the unassembled subunits in the cytoplasm. Even though these proteomic studies have helped to understand the molecular defects associated with leukodystrophy, how these mutations cause hypomyelination has yet to be defined. In this review we propose two main hypotheses to explain how mutations affecting Pol III subunits can cause hypomyelination.

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A variant of neonatal progeroid syndrome, or Wiedemann–Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL

Cited by 20 publications

References 27 publications

Premature aging disorders: A clinical and genetic compendium

Premature aging disorders: A clinical and genetic compendium

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

POLR3-related leukodystrophy: How do mutations affecting RNA polymerase III subunits cause hypomyelination?

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