Dataset Information

Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy.

ABSTRACT: Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs was performed for identification of the chromosomal locus for the disease. In the 14 Mb candidate region on chromosome 7q22, RNA expression profiling was used for selecting among the 203 genes in the area. In postmortem brain tissue available from one patient, histology and immunohistochemistry were performed. Disease course and imaging were mostly reminiscent of hypoxic-ischemic tetraplegic cerebral palsy, with neuroaxonal degeneration and white matter loss. In all five patients, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G-->T), was identified. AP4M1, encoding for the mu subunit of the adaptor protein complex-4, is involved in intracellular trafficking of glutamate receptors. Aberrant GluRdelta2 glutamate receptor localization and dendritic spine morphology were observed in the postmortem brain specimen. This disease entity, which we refer to as congenital spastic tetraplegia (CST), is therefore a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.

SUBMITTER: Verkerk AJ

PROVIDER: S-EPMC2706965 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy.

Verkerk Annemieke J M H AJ Schot Rachel R Dumee Belinda B Schellekens Karlijn K Swagemakers Sigrid S Bertoli-Avella Aida M AM Lequin Maarten H MH Dudink Jeroen J Govaert Paul P van Zwol A L AL Hirst Jennifer J Wessels Marja W MW Catsman-Berrevoets Coriene C Verheijen Frans W FW de Graaff Esther E de Coo Irenaeus F M IF Kros Johan M JM Willemsen Rob R Willems Patrick J PJ van der Spek Peter J PJ Mancini Grazia M S GM

American journal of human genetics 20090625 1

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs wa ...[more]

PMID: 19559397

Similar Datasets

Project description:Cerebral palsy is a neuromusculoskeletal disorder associated with muscle weakness, altered muscle architecture, and progressive musculoskeletal symptoms that worsen with age. Pathological changes at the level of the whole muscle have been shown; however, it is unclear why this progression of muscle impairment occurs at the cellular level. The process of muscle regeneration is complex, and the interactions between cells in the muscle milieu should be considered in the context of cerebral palsy. In this work, we built a coupled mechanobiological model of muscle damage and regeneration to explore the process of muscle regeneration in typical and cerebral palsy conditions, and whether a reduced number of satellite cells in the cerebral palsy muscle environment could cause the muscle regeneration cycle to lead to progressive degeneration of muscle. The coupled model consisted of a finite element model of a muscle fiber bundle undergoing eccentric contraction, and an agent-based model of muscle regeneration incorporating satellite cells, inflammatory cells, muscle fibers, extracellular matrix, fibroblasts, and secreted cytokines. Our coupled model simulated damage from eccentric contraction followed by 28 days of regeneration within the muscle. We simulated cyclic damage and regeneration for both cerebral palsy and typically developing muscle milieus. Here we show the nonlinear effects of altered satellite cell numbers on muscle regeneration, where muscle repair is relatively insensitive to satellite cell concentration above a threshold, but relatively sensitive below that threshold. With the coupled model, we show that the fiber bundle geometry undergoes atrophy and fibrosis with too few satellite cells and excess extracellular matrix, representative of the progression of cerebral palsy in muscle. This work uses in silico modeling to demonstrate how muscle degeneration in cerebral palsy may arise from the process of cellular regeneration and a reduced number of satellite cells.

Dataset Information

Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy.

Publications

Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets