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.
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"However, they mislocalize AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors and TARPs (transmembrane AMPA receptor regulatory proteins) to autophagosomes in the axons of Purkinje cells and hippocampal neurons . Despite the mild phenotype in mice, mutations of the four subunits of AP-4 in human all caused HSP (hereditary spastic paraplegia), a group of clinically and genetically heterogeneous disorders characterized by lower extremity spasticity and weakness, with or without other neurologic abnormalities [72–76]. Independent groups got this conclusion using different methods, including linkage analysis, microarray analysis or next-generation sequencing, strongly suggesting the important function of AP-4 in neurons. "
[Show abstract][Hide abstract]ABSTRACT: The Adaptor Protein (AP) complexes are heterotetrameric protein complexes that mediate intracellular membrane trafficking along endocytic and secretory transport pathways. There are five different AP complexes: AP-1, AP-2 and AP-3 are clathrin-associated complexes, while AP-4 and AP-5 are not. These five AP complexes localize to different intracellular compartments and mediate membrane trafficking in distinct pathways. They recognize and concentrate cargo proteins into vesicular carriers that mediate transport from a donor membrane to a target organellar membrane. AP complexes play import roles in maintaining the normal physiological function of eukaryotic cells. Dysfunction of AP complexes has been implicated in a variety of inherited disorders, including: MEDNIK syndrome, Fried syndrome, Hermansky-Pudlak syndrome (HPS) and hereditary spastic paraplegia (HSP).
Full-text · Article · Jun 2014 · Bioscience Reports
"Previously, mutations in two subunits, AP4M1 and AP4E1, of the adaptor protein complex 4 (AP4) were found associated with AR spastic tetraplegia as well as cerebral palsy and microcephaly, respectively (Verkerk et al., 2009; Moreno-De-Luca et al., 2011). But recently, pathogenic mutations in three AP4 subunits, AP4S1, AP4B1, and AP4E1, have also been identified in consanguineous families presenting with early-onset complex SPG, severe ID, microcephaly, inability to walk, and epilepsy (Abou Jamra et al., 2011); AP4B1 pathogenic mutations are also responsible for SPG type 47 (Bauer et al., 2012). "
[Show abstract][Hide abstract]ABSTRACT: New advances in genomic technology are being introduced at a greater speed and are revolutionizing the field of genetics for both complex and Mendelian diseases. For instance, during the past few years, genome-wide association studies (GWAS) have identified a large number of significant associations between genomic loci and movement disorders such as Parkinson's disease and progressive supranuclear palsy. GWAS are carried out through the use of high-throughput SNP genotyping arrays, which are also used to perform linkage analyses in families previously considered statistically underpowered for genetic analyses. In inherited movement disorders, using this latter technology, it has repeatedly been shown that mutations in a single gene can lead to different phenotypes, while the same clinical entity can be caused by mutations in different genes. This is being highlighted with the use of next-generation sequencing technologies and leads to the search for genes or genetic modifiers that contribute to the phenotypic expression of movement disorders. Establishing an accurate genome-epigenome-phenotype relationship is becoming a major challenge in the post-genomic research that should be facilitated through the implementation of both functional and cellular analyses.
Full-text · Article · May 2012 · Frontiers in Genetics
"PARK2, a gene of unknown function associated with related phenotypes such as Parkinson disease, nerve degeneration, cognition disorders, visual perception, attention, and memory, was abnormally expressed in schizophrenia and major depression [52,82-84]. AP4M1, which encodes a subunit of AP-4 complex responsible for transportation of proteins from Golgi, was abnormally expressed in schizophrenia and bipolar disorder [52,85]. Many of the genes were also found to be highly expressed in more than one disease as shown in Figure 3a. "
[Show abstract][Hide abstract]ABSTRACT: Schizophrenia, bipolar disorder, and major depression are devastating mental diseases, each with distinctive yet overlapping epidemiologic characteristics. Microarray and proteomics data have revealed genes which expressed abnormally in patients. Several single nucleotide polymorphisms (SNPs) and mutations are associated with one or more of the three diseases. Nevertheless, there are few studies on the interactions among the disease-associated genes and proteins.
This study, for the first time, incorporated microarray and protein-protein interaction (PPI) databases to construct the PPI network of abnormally expressed genes in postmortem brain samples of schizophrenia, bipolar disorder, and major depression patients. The samples were collected from Brodmann area (BA) 10 of the prefrontal cortex. Abnormally expressed disease genes were selected by t-tests comparing the disease and control samples. These genes were involved in housekeeping functions (e.g. translation, transcription, energy conversion, and metabolism), in brain specific functions (e.g. signal transduction, neuron cell differentiation, and cytoskeleton), or in stress responses (e.g. heat shocks and biotic stress).The diseases were interconnected through several "switchboard"-like nodes in the PPI network or shared abnormally expressed genes. A "core" functional module which consisted of a tightly knitted sub-network of clique-5 and -4s was also observed. These cliques were formed by 12 genes highly expressed in both disease and control samples.
Several previously unidentified disease marker genes and drug targets, such as SBNO2 (schizophrenia), SEC24C (bipolar disorder), and SRRT (major depression), were identified based on statistical and topological analyses of the PPI network. The shared or interconnecting marker genes may explain the shared symptoms of the studied diseases. Furthermore, the "switchboard" genes, such as APP, UBC, and YWHAZ, are proposed as potential targets for developing new treatments due to their functional and topological significance.
Full-text · Article · Nov 2011 · BMC Bioinformatics