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

Orphanet Journal of Rare Diseases

Frank Baas⁶  Bwee Tien Poll-Thé⁹  Henk A Marquering²  Charles BLM Majoie^1,17  Dirk Troost⁷  Eleonora Aronica⁷  Fred van Ruissen⁶  Mia T van Meegen⁶  Marit B Dijns-de Wissel⁶  Laszlo Sztriha³  Mohnish Suri^1,16  Louise Wilson⁴  Andrew N Williams^1,18  Sue Price^1,18  Declan O’Rourke^1,10  James AR Nicoll^1,12  Adrienn Máté^1,14  Periklis Makrythanasis¹  Mary D King^1,10  Thomas Jacques^1,13  Tibor Hortobágyi^1,15  Darren Fowler^1,11  Nicola Foulds^1,19  Joel Fluss⁸  Abhijit Dixit^1,16  Niklas Darin⁵  Jonathan N Berg^2,20  Jikke-Mien F Niermeijer⁹  Peter G Barth⁹  Veerle RC Eggens⁶ 

[1] Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland;Department of Biomedical Engineering and Physics, AMC, Amsterdam, the Netherlands;Department of Paediatrics, University of Szeged, Szeged, Hungary;Clinical Genetics, Great Ormond Street Hospital, London, UK;Department of Paediatrics, University of Gothenburg, The Queen Silvia’s Children Hospital, Gothenburg, Sweden;Department of Genome Analysis, Academic Medical Centre, Amsterdam, the Netherlands;Department of (Neuro)Pathology, Academic Center, University of the Netherlands, Amsterdam, the Netherlands;Pediatric Neurology, Children’s Hospital, Geneva, Switzerland;Division of Pediatric Neurology, Emma’s Children’s Hospital, Academic Medical Centre, Amsterdam, the Netherlands;Paediatric Neurology, Childrens University Hospital, Temple St., Dublin, Ireland;Paediatric Pathology, University Hospital Southampton NHS Trust, Southampton, UK;Clinical and Experimental Sciences, University of Southampton, Southampton, UK;Neural Development Unit, UCL Institute of Child Health and the Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK;Department of Neurosurgery, University of Szeged, Szeged, Hungary;Department of Neuropathology, Institute of Pathology, University of Debrecen, Debrecen, Hungary;Clinical Genetics, Nottingham City Hospital, Nottingham, UK;Department of Radiology, Academic Medical Center, Amsterdam, the Netherlands;Virtual Academic Unit, Child Development Centre, Northampton, Northants, UK;Clinical Genetics Service, Southampton University Hospitals Trust, Southampton, UK;Division of Pathology and Neuroscience, University of Dundee, Dundee, UK

关键词: Genotype-phenotype correlations;    EXOSC3 gene;    Neurodegeneration;    Pontocerebellar hypoplasia;   

Others  :  863252
DOI  :  10.1186/1750-1172-9-23

 received in 2013-10-31, accepted in 2014-02-06,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Eggens et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Barth PG: Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev 1993, 15:411-422.
• [2]Zanni G, Scotton C, Passarelli C, Fang M, Barresi S, Dallapiccola B, et al.: Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3. Neurogenetics 2013, 14:247-250.
• [3]Simonati A, Cassandrini D, Bazan D, Santorelli FM: TSEN54 mutation in a child with pontocerebellar hypoplasia type 1. Acta Neuropathol 2011, 121:671-673.
• [4]Namavar Y, Barth PG, Kasher PR, van RF, Brockmann K, Bernert G, et al.: Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain 2011, 134:143-156.
• [5]Renbaum P, Kellerman E, Jaron R, Geiger D, Segel R, Lee M, et al.: Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. Am J Hum Genet 2009, 85:281-289.
• [6]Wan J, Yourshaw M, Mamsa H, Rudnik-Schoneborn S, Menezes MP, Hong JE, et al.: Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet 2012, 44:704-708.
• [7]Rudnik-Schoneborn S, Senderek J, Jen JC, Houge G, Seeman P, Puchmajerova A, et al.: Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations. Neurology 2013, 80:438-446.
• [8]Biancheri R, Cassandrini D, Pinto F, Trovato R, Di RM, Mirabelli-Badenier M, et al.: EXOSC3 mutations in isolated cerebellar hypoplasia and spinal anterior horn involvement. J Neurol 2013, 260:1866-1870.
• [9]Schwabova J, Brozkova DS, Petrak B, Mojzisova M, Pavlickova K, Haberlova J, et al.: Homozygous EXOSC3 mutation c.92G-->C, p.G31A is a founder mutation causing severe Pontocerebellar Hypoplasia Type 1 among the Czech Roma. J Neurogenet 2013, 27:163-169.
• [10]Barth PG, Blennow G, Lenard HG, Begeer JH, van der Kley JM, Hanefeld F, et al.: The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly, and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled data from 10 pedigrees. Neurology 1995, 45:311-317.
• [11]Goutieres F, Aicardi J, Farkas E: Anterior horn cell disease associated with pontocerebellar hypoplasia in infants. J Neurol Neurosurg Psychiatry 1977, 40:370-378.
• [12]Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, et al.: User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage 2006, 31:1116-1128.
• [13]Goto N: Discriminative staining methods for the nervous system: luxol fast blue–periodic acid-Schiff–hematoxylin triple stain and subsidiary staining methods. Stain Technol 1987, 62:305-315.
• [14]de Leon GA, Grover WD, D'Cruz CA: Amyotrophic cerebellar hypoplasia: a specific form of infantile spinal atrophy. Acta Neuropathol 1984, 63:282-286.