POLR3A and POLR3B Mutations in Unclassified Hypomyelination

Cayami, Ferdy Kurniawan; Piana, Roberta La; Spaendonk, Rosalina M.L. van; Nickel, Miriam; Bley, Annette; Guerrero, Kether; Tran, Luan T.; Knaap, Marjo S. van der; Bernard, Geneviève; Wolf, Nicole I.

doi:10.1055/s-0035-1550148

Cited by 14 publications

(2 citation statements)

References 21 publications

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“…Interestingly, these families were mapped to the same locus as leukodystrophy with oligodontia and demonstrated clinical and radiological overlap with patients with hypomyelination, hypodontia and hypogonadotropic hypogonadism syndrome ( 138 ). Several other recent studies that followed also reported variants in the POLR3A gene as being responsible for causing hypomyelination, hypodontia and hypogonadotropic hypogonadism, thus establishing a series of POLR3A gene variants to be associated with polymerase III-related leukodystrophy ( 139 – 144 ). It is estimated that 30–40% of patients with leukodystrophies remain without a molecular diagnosis ( 138 , 141 ).…”

Section: Review Of the Literaturementioning

confidence: 90%

GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature

et al. 2020

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Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease caused by Gonadotropin-Releasing Hormone (GnRH) deficiency. So far a limited number of variants in several genes have been associated with the pathogenesis of the disease. In this original research and review manuscript the retrospective analysis of known variants in ANOS1 ( KAL1), RNF216, WDR11, FGFR1, CHD7 , and POLR3A genes is described, along with novel variants identified in patients with CHH by the present study. Methods: Seven GnRH deficient unrelated Cypriot patients underwent whole exome sequencing (WES) by Next Generation Sequencing (NGS). The identified novel variants were initially examined by in silico computational algorithms and structural analysis of their predicted pathogenicity at the protein level was confirmed. Results: In four non-related GnRH males, a novel X-linked pathogenic variant in ANOS1 gene, two novel autosomal dominant (AD) probably pathogenic variants in WDR11 and FGFR1 genes and one rare AD probably pathogenic variant in CHD7 gene were identified. A rare autosomal recessive (AR) variant in the SRA1 gene was identified in homozygosity in a female patient, whilst two other male patients were also, respectively, found to carry novel or previously reported rare pathogenic variants in more than one genes; FGFR1 / POLR3A and SRA1/RNF216 . Conclusion: This report embraces the description of novel and previously reported rare pathogenic variants in a series of genes known to be implicated in the biological development of CHH. Notably, patients with CHH can harbor pathogenic rare variants in more than one gene which raises the hypothesis of locus-locus interactions providing evidence for digenic inheritance. The identification of such aberrations by NGS can be very informative for the management and future planning of these patients.

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Section: Review Of the Literaturementioning

confidence: 90%

GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature

et al. 2020

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“…Since the initial identification of mutations in POLR3A [1], more than 100 mutations in POLR3A , POLR3B and POLR1C have been identified in over 130 patients with POLR3-HLD [1–5, 8, 10–19]. The majority of mutations are private or present in only a handful of patients [5].…”

Section: Introductionmentioning

confidence: 99%

Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation

et al. 2017

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Recessive mutations in the ubiquitously expressed POLR3A gene cause one of the most frequent forms of childhood-onset hypomyelinating leukodystrophy (HLD): POLR3-HLD. POLR3A encodes the largest subunit of RNA Polymerase III (Pol III), which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs. In order to study the central nervous system pathophysiology of the disease, we introduced the French Canadian founder Polr3a mutation c.2015G > A (p.G672E) in mice, generating homozygous knock-in (KI/KI) as well as compound heterozygous mice for one Polr3a KI and one null allele (KI/KO). Both KI/KI and KI/KO mice are viable and are able to reproduce. To establish if they manifest a motor phenotype, WT, KI/KI and KI/KO mice were submitted to a battery of behavioral tests over one year. The KI/KI and KI/KO mice have overall normal balance, muscle strength and general locomotion. Cerebral and cerebellar Luxol Fast Blue staining and measurement of levels of myelin proteins showed no significant differences between the three groups, suggesting that myelination is not overtly impaired in Polr3a KI/KI and KI/KO mice. Finally, expression levels of several Pol III transcripts in the brain showed no statistically significant differences. We conclude that the first transgenic mice with a leukodystrophy-causing Polr3a mutation do not recapitulate the childhood-onset HLD observed in the majority of human patients with POLR3A mutations, and provide essential information to guide selection of Polr3a mutations for developing future mouse models of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-017-0294-y) contains supplementary material, which is available to authorized users.

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Wiedemann–Rautenstrauch syndrome: A phenotype analysis

Paolacci

Bertola

Franco

et al. 2017

American J of Med Genetics Pt A

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Wiedemann-Rautenstrauch syndrome (WRS) is a neonatal progeroid disorder characterized by growth retardation, lipodystrophy, a distinctive face, and dental anomalies. Patients reported to date demonstrate a remarkable variability in phenotype, which hampers diagnostics. We performed a literature search, and analyzed 51 reported patients, using the originally reported patients as "gold standard." In 15 patients sufficient information and photographic evidence was available to confirm the clinical diagnosis. In 12 patients the diagnosis was suggestive but lack of data prevented a definite diagnosis, and in 24 patients an alternative diagnosis was likely. Core manifestations of the syndrome are marked pre-natal and severe post-natal growth retardation, an unusual face (triangular shape, sparse hair, small mouth, pointed chin), dental anomalies (natal teeth; hypodontia), generalized lipodystrophy with localized fat masses, and-in some cases-progressive ataxia and tremor. It has been suggested that the syndrome might be caused by biallelic variants in POLR3A, identified by exome sequencing in a single patient only. Therefore, we compared the WRS phenotype with characteristics of conditions known to be caused by autosomal recessively inherited POLR3A mutations. There are major differences but there are also similarities in phenotype, which sustain the suggestion that the syndrome can be caused by disturbed POLR3A functioning.

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POLR3A and POLR3B Mutations in Unclassified Hypomyelination

Abstract: Mutations in POLR3A or POLR3B are rare in patients with unclassified hypomyelination, and alternative diagnoses should be considered first.

Cited by 14 publications

References 21 publications

GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature

GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature

Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation

Wiedemann–Rautenstrauch syndrome: A phenotype analysis

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