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

EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations
EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations
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.
pontocerebellar hypoplasia, neurodegeneration, EXOSC3 gene, genotype-phenotype correlations
1750-1172
Eggens, Veerle R.C.
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Barth, Peter G.
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Niermeijer, Jikke-Mien F.
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Berg, Jonathan N.
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Darin, Niklas
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Dixit, Abhijit
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Fluss, Joel
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Foulds, Nicola
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Fowler, Darren
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Hortobágyi, Tibor
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Jacques, Thomas
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King, Mary D.
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Makrythanasis, Periklis
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Máté, Adrienn
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Nicoll, James A.R.
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O'Rourke, Declan
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Price, Sue
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Williams, Andrew N.
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Wilson, Louise
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Suri, Mohnish
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Sztriha, Laszlo
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Dijns-de Wissel, Marit B.
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van Meegen, Mia T.
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van Ruissen, Fred
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Aronica, Eleonora
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Troost, Dirk
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Majoie, Charles B.L.M.
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Marquering, Henk A.
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Poll-Thé, Bwee Tien
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Baas, Frank
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Eggens, Veerle R.C.
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Barth, Peter G.
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Niermeijer, Jikke-Mien F.
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Berg, Jonathan N.
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Darin, Niklas
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Dixit, Abhijit
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Fluss, Joel
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Foulds, Nicola
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Fowler, Darren
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Hortobágyi, Tibor
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Jacques, Thomas
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King, Mary D.
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Makrythanasis, Periklis
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Máté, Adrienn
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Nicoll, James A.R.
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O'Rourke, Declan
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Price, Sue
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Williams, Andrew N.
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Wilson, Louise
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Suri, Mohnish
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Sztriha, Laszlo
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Dijns-de Wissel, Marit B.
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van Meegen, Mia T.
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van Ruissen, Fred
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Aronica, Eleonora
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Troost, Dirk
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Majoie, Charles B.L.M.
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Marquering, Henk A.
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Poll-Thé, Bwee Tien
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Baas, Frank
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Eggens, Veerle R.C., 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 A.R., 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 B.L.M., Marquering, Henk A., Poll-Thé, Bwee Tien and Baas, Frank (2014) EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations. Orphanet Journal of Rare Diseases, 9 (1), part 23, [23 (2014)]. (doi:10.1186/1750-1172-9-23). (PMID:24524299)

Record type: Article

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.

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Accepted/In Press date: 6 February 2014
e-pub ahead of print date: 13 February 2014
Published date: 13 February 2014
Keywords: pontocerebellar hypoplasia, neurodegeneration, EXOSC3 gene, genotype-phenotype correlations
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 362240
URI: http://eprints.soton.ac.uk/id/eprint/362240
ISSN: 1750-1172
PURE UUID: 1adc1990-841b-4f7b-b880-37e74d62808c
ORCID for James A.R. Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

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Date deposited: 19 Feb 2014 10:17
Last modified: 15 Mar 2024 03:13

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Contributors

Author: Veerle R.C. Eggens
Author: Peter G. Barth
Author: Jikke-Mien F. Niermeijer
Author: Jonathan N. Berg
Author: Niklas Darin
Author: Abhijit Dixit
Author: Joel Fluss
Author: Nicola Foulds
Author: Darren Fowler
Author: Tibor Hortobágyi
Author: Thomas Jacques
Author: Mary D. King
Author: Periklis Makrythanasis
Author: Adrienn Máté
Author: Declan O'Rourke
Author: Sue Price
Author: Andrew N. Williams
Author: Louise Wilson
Author: Mohnish Suri
Author: Laszlo Sztriha
Author: Marit B. Dijns-de Wissel
Author: Mia T. van Meegen
Author: Fred van Ruissen
Author: Eleonora Aronica
Author: Dirk Troost
Author: Charles B.L.M. Majoie
Author: Henk A. Marquering
Author: Bwee Tien Poll-Thé
Author: Frank Baas

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