Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.

OBJECTIVE: To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment. METHODS: Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire. RESULTS: 7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion). CONCLUSIONS: Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome.

Burkitt lymphoma in the mouse.

Chromosomal translocations juxtaposing the MYC protooncogene with regulatory sequences of immunoglobulin (Ig) H chain or kappa (Ig kappa) or lambda (Ig lambda) L chain genes and effecting deregulated expression of MYC are the hallmarks of human Burkitt lymphoma (BL). Here we report that lymphomas with striking similarities to BL develop in mice bearing a mutated human MYC gene controlled by a reconstructed Ig lambda locus encompassing all the elements required for establishment of locus control in vitro. Diffusely infiltrating lymphomas with a typical starry sky appearance occurred in multiple founders and an established line, indicating independence from positional effects. Monoclonal IgM(+)CD5(-)CD23(-) tumors developed from an initially polyclonal population of B cells. These results demonstrate that the phenotype of B lineage lymphomas induced by MYC dysregulation is highly dependent on cooperativity among the regulatory elements that govern expression of the protooncogene and provide a new system for studying the pathogenesis of BL.

MITOP, the mitochondrial proteome database: 2000 update.

MITOP (http://www.mips.biochem.mpg.de/proj/medgen/mitop/) is a comprehensive database for genetic and functional information on both nuclear- and mitochondrial-encoded proteins and their genes. The five species files--Saccharomyces cerevisiae, Mus musculus, Caenorhabditis elegans, Neurospora crassa and Homo sapiens--include annotated data derived from a variety of online resources and the literature. A wide spectrum of search facilities is given in the overlapping sections 'Gene catalogues', 'Protein catalogues', 'Homologies', 'Pathways and metabolism' and 'Human disease catalogue' including extensive references and hyperlinks to other databases. Central features are the results of various homology searches, which should facilitate the investigations into interspecies relationships. Precomputed FASTA searches using all the MITOP yeast protein entries and a list of the best human EST hits with graphical cluster alignments related to the yeast reference sequence are presented. The orthologue tables with cross-listings to all the protein entries for each species in MITOP have been expanded by adding the genomes of Rickettsia prowazeckii and Escherichia coli. To find new mitochondrial proteins the complete yeast genome has been analyzed using the MITOPROT program which identifies mitochondrial targeting sequences. The 'Human disease catalogue' contains tables with a total of 110 human diseases related to mitochondrial protein abnormalities, sorted by clinical criteria and age of onset. MITOP should contribute to the systematic genetic characterization of the mitochondrial proteome in relation to human disease.

Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency.

Mutations of SURF-1, a gene located on chromosome 9q34, have recently been identified in patients affected by Leigh syndrome (LS), associated with deficiency of cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain. To investigate to what extent SURF-1 is responsible for human disorders because of COX deficiency, we undertook sequence analysis of the SURF-1 gene in 46 unrelated patients. We analyzed 24 COX-defective patients classified as having typical Leigh syndrome (LS(COX)), 6 patients classified as Leigh-like (LL(COX)) cases, and 16 patients classified as non-LS(COX) cases. Frameshift, stop, and splice mutations of SURF-1 were detected in 18 of 24 (75%) of the LS(COX) cases. No mutations were found in the LL(COX) and non-LS(COX) group of patients. Rescue of the COX phenotype was observed in transfected cells from patients harboring SURF-1 mutations, but not in transfected cell lines from 2 patients in whom no mutations were detected by sequence analysis. Loss of function of SURF-1 protein is specifically associated with LS(COX), although a proportion of LS(COX) cases must be the result of abnormalities in genes other than SURF-1. SURF-1 is the first nuclear gene to be consistently mutated in a major category of respiratory chain defects. DNA analysis can now be used to accurately diagnose LS(COX), a common subtype of Leigh syndrome.

MITOP: database for mitochondria-related proteins, genes and diseases.

The MITOP database http://websvr.mips.biochem.mpg. de/proj/medgen/mitop/ consolidates information on both nuclear- and mitochondrial-encoded genes and their proteins. The five species files- Saccharomyces cerevisiae, Mus musculus, Caenorhabditis elegans, Neurospora crassa and Homo sapiens -include annotated data derived from a variety of online resources and the literature. A wide spectrum of search facilities is given in the interelated sections 'Gene catalogues', 'Protein catalogues', 'Homologies', 'Pathways and metabolism', and 'Human disease catalogue' including extensive references and hyperlinks for each entry. Precomputed FASTA searches using all the MITOP yeast protein entries and a list of the best EST hits with graphical cluster alignments related to the yeast reference sequence are presented. The MITOP orthologue tables with cross-listing to all the protein entries for each species in the database facilitate investigations into interspecies homology. A program (MITOPROT) is available to identify mitochondrial targeting sequences and graphical depictions of several important mitochondrial processes are included. The 'Human disease catalogue' lists a total of 101 disorders related to mitochondrial protein abnormalities, sorted by clinical criteria and age of onset.

Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.

Leigh disease associated with cytochrome c oxidase deficiency (LD[COX-]) is one of the most common disorders of the mitochondrial respiratory chain, in infancy and childhood. No mutations in any of the genes encoding the COX-protein subunits have been identified in LD(COX-) patients. Using complementation assays based on the fusion of LD(COX-) cell lines with several rodent/human rho0 hybrids, we demonstrated that the COX phenotype was rescued by the presence of a normal human chromosome 9. Linkage analysis restricted the disease locus to the subtelomeric region of chromosome 9q, within the 7-cM interval between markers D9S1847 and D9S1826. Candidate genes within this region include SURF-1, the yeast homologue (SHY-1) of which encodes a mitochondrial protein necessary for the maintenance of COX activity and respiration. Sequence analysis of SURF-1 revealed mutations in numerous DNA samples from LD(COX-) patients, indicating that this gene is responsible for the major complementation group in this important mitochondrial disorder.