EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations

Hdl Handle:
http://hdl.handle.net/10147/315481
Title:
EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations
Authors:
Eggens, Veerle RC; Barth, Peter G; Niermeijer, Jikke-Mien F; Berg, Jonathan N; Darin, Niklas; Dixit, Abhijit; Fluss, Joel; Foulds, Nicola; Fowler, Darren; Hortobágyi, Tibor; Jacques, Thomas; King, Mary D; Makrythanasis, Periklis; Máté, Adrienn; Nicoll, James AR; O’Rourke, Declan; Price, Sue; Williams, Andrew N; Wilson, Louise; Suri, Mohnish; Sztriha, Laszlo; Dijns-de Wissel, Marit B; van Meegen, Mia T; van Ruissen, Fred; Aronica, Eleonora; Troost, Dirk; Majoie, Charles BLM; Marquering, Henk A; Poll-Thé, Bwee T; Baas, Frank
Citation:
Orphanet Journal of Rare Diseases. 2014 Feb 13;9(1):23
Issue Date:
13-Feb-2014
URI:
http://dx.doi.org/10.1186/1750-1172-9-23; http://hdl.handle.net/10147/315481
Abstract:
Abstract Background Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. Methods We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. Results EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. Conclusions EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.
Item Type:
Article
Language:
en
Keywords:
GENETICS; NEUROLOGICAL DISEASES AND DISORDER

Full metadata record

DC FieldValue Language
dc.contributor.authorEggens, Veerle RCen_GB
dc.contributor.authorBarth, Peter Gen_GB
dc.contributor.authorNiermeijer, Jikke-Mien Fen_GB
dc.contributor.authorBerg, Jonathan Nen_GB
dc.contributor.authorDarin, Niklasen_GB
dc.contributor.authorDixit, Abhijiten_GB
dc.contributor.authorFluss, Joelen_GB
dc.contributor.authorFoulds, Nicolaen_GB
dc.contributor.authorFowler, Darrenen_GB
dc.contributor.authorHortobágyi, Tiboren_GB
dc.contributor.authorJacques, Thomasen_GB
dc.contributor.authorKing, Mary Den_GB
dc.contributor.authorMakrythanasis, Periklisen_GB
dc.contributor.authorMáté, Adriennen_GB
dc.contributor.authorNicoll, James ARen_GB
dc.contributor.authorO’Rourke, Declanen_GB
dc.contributor.authorPrice, Sueen_GB
dc.contributor.authorWilliams, Andrew Nen_GB
dc.contributor.authorWilson, Louiseen_GB
dc.contributor.authorSuri, Mohnishen_GB
dc.contributor.authorSztriha, Laszloen_GB
dc.contributor.authorDijns-de Wissel, Marit Ben_GB
dc.contributor.authorvan Meegen, Mia Ten_GB
dc.contributor.authorvan Ruissen, Freden_GB
dc.contributor.authorAronica, Eleonoraen_GB
dc.contributor.authorTroost, Dirken_GB
dc.contributor.authorMajoie, Charles BLMen_GB
dc.contributor.authorMarquering, Henk Aen_GB
dc.contributor.authorPoll-Thé, Bwee Ten_GB
dc.contributor.authorBaas, Franken_GB
dc.date.accessioned2014-04-07T11:43:57Z-
dc.date.available2014-04-07T11:43:57Z-
dc.date.issued2014-02-13-
dc.identifier.citationOrphanet Journal of Rare Diseases. 2014 Feb 13;9(1):23en_GB
dc.identifier.urihttp://dx.doi.org/10.1186/1750-1172-9-23-
dc.identifier.urihttp://hdl.handle.net/10147/315481-
dc.description.abstractAbstract Background Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. Methods We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. Results EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. Conclusions EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.-
dc.language.isoenen
dc.subjectGENETICSen_GB
dc.subjectNEUROLOGICAL DISEASES AND DISORDERen_GB
dc.titleEXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlationsen_GB
dc.typeArticleen
dc.language.rfc3066en-
dc.rights.holderVeerle RC Eggens et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2014-04-05T11:20:16Z-
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