Hostname: page-component-586b7cd67f-dsjbd Total loading time: 0 Render date: 2024-11-28T14:29:52.472Z Has data issue: false hasContentIssue false
  • English
  • Français

A Novel PLP1 Mutation Further Expands the Clinical Heterogeneity at the Locus

Published online by Cambridge University Press:  02 December 2014

Collette Kathleen Hand ,
Geneviève Bernard ,
Marie-Pierre Dubé ,
Michael Israel Shevell  and
Guy Armand Rouleau
Collette Kathleen Hand
Affiliation:
Department of Pathology, University College Cork, Ireland
Geneviève Bernard
Affiliation:
Department of Neurology and Neurosurgery, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre
Marie-Pierre Dubé
Affiliation:
Research Centre of the Montreal Heart Institute
Michael Israel Shevell
Affiliation:
Department of Neurology and Neurosurgery, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre
Guy Armand Rouleau*
Affiliation:
Department of Medicine, Center of Excellence in Neuromics, Université de Montréal, Montreal, Quebec, Canada
*
Center of Excellence in Neuromics of Université de Montréal, CHUM Research Center, J.A. de Sève Pavilion, Room Y-3633, 1560, Sherbrooke Street East, Montreal, QC, H2L 4M1, Canada.
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
Objectives:

To characterize at clinical and molecular levels a family presenting with X-linked recessive Hereditary Spastic Paraplegia (HSP).

Background:

HSPs are a large group of genetically heterogeneous neurodegenerative disorders characterized by progressive upper motor neuron signs. Mutations in the proteolipid protein (PLP1) gene have been identified in families linked to the SPG2 locus on chromosome Xq22. However, Pelizaeus-Merzbacher disease (PMD) is also an X-linked recessive neurological disorder caused by PLP1 mutations.

Methods:

The SPG2 locus was investigated by linkage analysis in the family. The PLP1 gene was screened by sequencing. We present findings in a large French-Canadian family with an X-linked recessive HSP. The proband presented early with developmental delay and developed progressive spastic paraplegia. He has been wheelchair-bound since the age of three years. At the latest follow-up, he was 20 years-old and had severe spasticity predominantly affecting the lower extremities, moderate cerebellar dysfunction, and optic atrophy.

Results:

Linkage to SPG2 was established and a G to A mutation (M1R) in the initiation codon of the PLP1 gene was identified, likely resulting in the complete absence of proteolipid protein.

Conclusion:

We report a new PLP1 gene mutation in a patient with a clinical phenotype consistent with a PLP1 null syndrome.

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 39 , Issue 2 , March 2012 , pp. 220 - 224
Copyright
Copyright © The Canadian Journal of Neurological 2012

References

1Jouet, M, Rosenthal, A, Armstrong, G, et al.X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet. 1994;7(3):402–7.Google Scholar
2Saugier-Veber, P, Munnich, A, Bonneau, D, et al.X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet. 1994;6(3):257–62.Google Scholar
3Steinmüller, R, Lantigua-Cruz, A, Garcia-Garcia, R, Kostrzewa, M, Steinberger, D, Müller, U.Evidence of a third locus in X-linked recessive spastic paraplegia. Hum Genet. 1997;100(2):287–9.Google ScholarPubMed
4Tamagaki, A, Shima, M, Tomita, R, et al.Segregation of a pure form of spastic paraplegia and NOR insertion into Xq11.2. Am J Med Genet. 2000;94(1):5–8.Google Scholar
5Macedo-Souza, LI, Kok, F, Santos, S, et al.Reevaluation of a large family defines a new locus for X-linked recessive pure spastic paraplegia (SPG34) on chromosome Xq25. Neurogenetics. 2008;9(3):225–6.Google Scholar
6Hudson, LD, Puckett, C, Berndt, J, Chan, J, Gencic, S.Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder. Proc Natl Acad Sci USA. 1989;86(20):8128–31.Google Scholar
7Inoue, K.PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics. 2005;6(1):1–16.Google Scholar
8Inoue, K, Osaka, H, Imaizumi, K, et al.Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: molecular mechanism and phenotypic manifestations. Ann Neurol. 1999;45(5):624–32.Google Scholar
9Sistermans, EA, de Wijs, IJ, de Coo, RF, Smit, LM, Menko, FH, van Oost, BA.A (G-to-A) mutation in the initiation codon of the proteolipid protein gene causing a relatively mild form of Pelizaeus-Merzbacher disease in a Dutch family. Hum Genet. 1996;97(3):337–9.Google Scholar
Mimault, C, Giraud, G, Courtois, V, et al.Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher Disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. The Clinical European Network on Brain Dysmyelinating Disease. Am J Hum Genet. 1999;65(2):360–9.Google Scholar
11Raskind, WH, Williams, CA, Hudson, LD, Bird, TD.Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease. Am J Hum Genet. 1991;49(6):1355–60.Google Scholar
12Sistermans, EA, de Coo, RF, De Wijs, IJ, Van Oost, BA.Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology. 1998;50(6):1749–54.Google Scholar
13Boulloche, J, Aicardi, J.Pelizaeus-Merzbacher disease: clinical and nosological study. J Child Neurol. 1986;1(3):233–9.CrossRefGoogle ScholarPubMed
14Cailloux, F, Gauthier-Barichard, F, Mimault, C, et al.Genotypephenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease. Eur J Hum Genet. 2000;8(11):837–45.Google Scholar
15Hodes, M, Pratt, V, Dlouhy, S.Genetics of Pelizaeus-Merzbacher disease. Dev Neurosci. 1993;15(6):383–94.Google Scholar
16Nave, K, Lai, C, Bloom, F, Milner, R.Splice site selection in the proteolipid protein (PLP) gene transcript and primary structure of the DM-20 protein of central nervous system myelin. Proc Natl Acad Sci USA. 1987;84(16):5665–9.Google Scholar
17Bonneau, D, Rozet, JM, Bulteau, C, et al.X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus. J Med Genet. 1993;30(5):381–4.Google Scholar
18Garbern, JY, Cambi, F, Tang, X-M, et al.Proteolipid protein is necessary in peripheral as well as central myelin. Neuron. 1997;19(1):205–18.Google Scholar
19Garbern, JY, Yool, DA, Moore, GJ, et al.Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain. 2002;125(3):551–61.Google Scholar