PubMed Health⌕ Search

Biomedical subjects

A E Lehesjoki

Publications and source records attributed to A E Lehesjoki.

At least 19 recordsLinked to original sources
PubMed2002

Brainstem involvement in Unverricht-Lundborg disease (EPM1): An MRI and (1)H MRS study.

MRI of the brain and proton MRS ((1)H MRS) of the pons and dentate were obtained in 10 patients with genetically confirmed Unverricht-Lundborg disease (EPM1) and 20 control subjects. Patients with EPM1 showed (p < or = 0.01) loss of bulk of the basis pontis, medulla, and cerebellar hemispheres. Cerebral atrophy was present in six patients. The N-acetylaspartate/creatine and choline/creatine ratios were reduced in the pons but not in the dentate (p < or = 0.005). Brainstem involvement could play a role in pathophysiology of EPM1.

Adolescent↗
PubMed2001

Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3.

Usher syndrome type 3 (USH3) is an autosomal recessive disorder characterized by progressive hearing loss, severe retinal degeneration, and variably present vestibular dysfunction, assigned to 3q21-q25. Here, we report on the positional cloning of the USH3 gene. By haplotype and linkage-disequilibrium analyses in Finnish carriers of a putative founder mutation, the critical region was narrowed to 250 kb, of which we sequenced, assembled, and annotated 207 kb. Two novel genes-NOPAR and UCRP-and one previously identified gene-H963-were excluded as USH3, on the basis of mutational analysis. USH3, the candidate gene that we identified, encodes a 120-amino-acid protein. Fifty-two Finnish patients were homozygous for a termination mutation, Y100X; patients in two Finnish families were compound heterozygous for Y100X and for a missense mutation, M44K, whereas patients in an Italian family were homozygous for a 3-bp deletion leading to an amino acid deletion and substitution. USH3 has two predicted transmembrane domains, and it shows no homology to known genes. As revealed by northern blotting and reverse-transcriptase PCR, it is expressed in many tissues, including the retina.

Abnormalities, Multiple↗
PubMed2001

Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease.

BACKGROUND: Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial. The MEB gene is located on chromosome 1p32-p34. OBJECTIVES: To establish distinguishing diagnostic criteria for MEB and WWS and to determine whether MEB and WWS are allelic disorders. METHODS: The authors undertook clinical characterization followed by linkage analysis in 19 MEB/WWS families with 29 affected individuals. With use of clinical diagnostic criteria based on Finnish patients with MEB, each patient was categorized as having either MEB or WWS. A linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource. RESULTS: Patients in 11 families were classified as having MEB and in 8 families as WWS. Strong evidence in favor of genetic heterogeneity was obtained in the 19 families. There was evidence for linkage to 1p32-p34 in all but 1 of the 11 pedigrees segregating the MEB phenotype. In contrast, linkage to the MEB locus was excluded in seven of eight of the WWS families. CONCLUSION: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).

Adolescent↗
PubMed2001

Turkish variant late infantile neuronal ceroid lipofuscinosis (CLN7) may be allelic to CLN8.

One variant form of late infantile neuronal ceroid lipofuscinosis (LINCL) is found predominantly within the Turkish population (CLN7). Exclusion mapping showed that CLN7 was not an allelic variant of known NCL loci (CLN1, CLN2, CLN3, CLN5 or CLN6). Using the method of homozygosity mapping, a genome-wide search was undertaken and a total of 358 microsatellite markers were typed at an average distance of about 10 cM. A region of shared homozygosity was identified on chromosome 8p23. This telomeric region contained the recently identified CLN8 gene. A missense mutation in CLN8 causes progressive epilepsy with mental retardation (EPMR) or Northern epilepsy, which has so far been reported only from Finland and is now classified as an NCL. The mouse model mnd has been shown to carry a 1 bp insertion in the orthologous Cln8 gene. Statistically significant evidence for linkage was obtained in this region, with LOD scores > 3, assuming either homogeneity or heterogeneity. Flanking recombinants defined a critical region of 14 cM between D8S504 and D8S1458 which encompasses CLN8. This suggests that Turkish variant LINCL, despite having an earlier onset and more severe phenotype, may be an allelic variant of Northern epilepsy. However mutation analysis has not so far identified a disease causing mutation within the coding or non-coding exons of CLN8 in the families. The Turkish variant LINCL disease-causing mutation remains to be delineated.

Alleles↗
PubMed2000

The neuronal ceroid lipofuscinosis CLN8 membrane protein is a resident of the endoplasmic reticulum.

Progressive epilepsy with mental retardation (EPMR) is a new member of the neuronal ceroid lipofuscinoses (NCLs). The CLN8 gene underlying EPMR was recently identified. It encodes a novel 286 amino acid transmembrane protein that contains an endoplasmic reticulum (ER)-retrieval signal (KKRP) in its C-terminus. A homozygous mutation in the orthologous mouse gene (Cln8) underlies the phenotype of a naturally occurring NCL model, the motor neuron degeneration mouse (mnd). To characterize the product of the CLN8 gene and to determine its intracellular localization, we expressed CLN8 cDNA in BHK, HeLa and CHO cell lines. In western blotting and pulse-chase analyses an approximately 33 kDa protein that does not undergo proteolytic processing steps was detected. Using CLN8 and cell organelle specific antibodies with confocal immunofluorescence microscopy the CLN8 protein was shown to localize in the ER. Partial localization to the ER-Golgi intermediate compartment (ERGIC) was also observed. The ER-ERGIC localization was not altered in the CLN8 protein representing the EPMR mutation. However, mnd mutant protein was only found in the ER. Mutations in the ER retrieval signal KKRP resulted in localization of CLN8 to the Golgi apparatus. Taken together, these data strongly suggest that CLN8 is an ER resident protein that recycles between ER and ERGIC.

Amino Acid Motifs↗
PubMed2000

A sequence-ready map of the Usher syndrome type III critical region on chromosome 3q.

Usher syndrome type 3 (USH3; MIM 276902) is an autosomal recessive disorder associated with progressive hearing loss and retinal degeneration. We recently refined the localization of USH3 to a 1-cM genetic interval between markers D3S1299 and D3S3625. We have now constructed a bacterial artificial chromosome contig over the region. Novel polymorphic markers were generated and physically fine-mapped, allowing further narrowing of the critical interval to a 250-kb genomic fragment. Of seven ESTs mapping to the initial critical region, WI-11588 and SHGC-133 represent the human SIAH2 gene, which was excluded as a candidate for USH3 by sequencing and subsequently, by its position. KIAA0001 and D3S3882 derive from the transcript of a putative G-protein-coupled receptor gene that was excluded as a candidate by sequencing of patient DNA. These data provide a basis for the sequencing and final characterization of the USH3 region and isolation of the disease gene.

Chromosomes, Bacterial↗
PubMed2000

Characterization of the cystatin B gene promoter harboring the dodecamer repeat expanded in progressive myoclonus epilepsy, EPM1.

Mutations in the gene encoding cystatin B (CSTB) are responsible for the primary defect in progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1). A novel and unique type of disease-causing mutation, an unstable dodecamer repeat expansion, accounts for the majority of EPM1 patients world-wide. This minisatellite repeat expansion, located in the putative promoter of CSTB 175 bp upstream from the translation initiation codon, appears to downregulate CSTB gene expression in vivo. We report here the characterization of the CSTB promoter using different promoter-luciferase gene constructs. Transient transfections of cultured mammalian cells suggest that the region from -670 to -1 bp from the translation initiation codon functions as the CSTB promoter. Active binding to five Sp1 and four AP1 sites as well as weak binding to an androgen response element (ARE) half site was demonstrated by electrophoretic mobility shift assays. The effect of the minisatellite expansion on the promoter activity was evaluated by comparing the activity of constructs containing wild-type and expanded alleles. An increase in the number of dodecamer units from three to 19 repeats lowered transcription in vitro by 10-fold. Northern analysis of lymphoblastoid RNA from individuals with 'premutation' length dodecamer repeat (12-17 copies) expansions showed decreased levels of CSTB mRNA expression. These data indicate that expansion of the dodecamer repeat located in the proximal promoter of CSTB severely disrupts the function of the promoter and thereby reduces transcription of CSTB.

Animals↗
PubMed2000

A patient with 2 different repeat expansion mutations.

BACKGROUND: Many inherited progressive encephalopathies have a poor outcome, and some are caused by repeat expansion mutations. How would the presence of 2 different expansion mutations affect the phenotype? OBJECTIVE: To describe a patient who has 2 distinct, rare genetic disorders: myotonic dystrophy (DM, OMIM 160900) and progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1, OMIM 254800). Both conditions are caused by repeat expansion mutations. They affect the central nervous system causing mental retardation, but also produce a wide spectrum of disabilities in daily living. SETTING: Referral center. METHODS: Clinical description with accompanying photographs, electroencephalography and magnetic resonance imaging; DNA analysis of both of the mutations and chromosomal analysis with prometaphase spreads. RESULTS: The patient had clinical characteristics and findings of both myotonic dystrophy and progressive myoclonus epilepsy of the Unverricht-Lundborg type. Electroencephalographic recordings over a 3-year period showed typical findings for myoclonus epilepsy. The patient had no gross anomalies in brain magnetic resonance imaging. She had a normal karyotype, and both of the diagnoses were confirmed at the molecular level with the direct detection of the mutations. CONCLUSIONS: Despite having 2 different progressive inherited disorders affecting the central nervous system, the patient, at age 28 years, showed only mild mental retardation with very slow progression. However, clear deterioration in activities of daily living has taken place during last 3 years. Arch Neurol. 2000;57:1199-1203

Adult↗
PubMed2000

Northern epilepsy, a new member of the NCL family.

Northern epilepsy, or progressive epilepsy with mental retardation (EPMR), is an autosomal recessive disorder characterized by normal early development, onset of generalized tonic-clonic seizures between the ages of 5 and 10 years, and subsequent progressive mental retardation. The seizures increase in frequency until puberty after which the epileptic activity starts to decline. Mental retardation begins 2-5 years after the onset of seizures and continues through adulthood. Neuropathological findings have shown that EPMR is a new member (CLN8) of the neuronal ceroid lipofuscinosis (NCL) group of neurodegenerative disorders. The CLN8 gene was identified recently. It encodes a 286 amino acid putative transmembrane protein with no homology to previously known proteins. Subsequently, the homologous mouse gene (Cln8) was sequenced and localized to the region of the mouse genome linked to motor neuron degeneration, mouse mnd. Mnd is a naturally occurring mouse mutant with intracellular autofluorescent inclusions similar to those seen in human CLN8. A mutation in mnd mouse DNA was identified, indicating that mnd is a murine model for CLN8.

Animals↗
PubMed2000

Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts unlinked to the LAMA2, FCMD and MEB loci.

We report a case of congenital muscular dystrophy with secondary merosin deficiency, structural involvement of the central nervous system and mental retardation in an 8-year-old girl from a consanguineous family. She had early-onset hypotonia, generalized muscle wasting, with weakness especially of the neck muscles, joint contractures, mental retardation and high creatine kinase. Muscle biopsy showed dystrophic changes with partial deficiency of the laminin alpha(2) chain. Cranial magnetic resonance imaging revealed multiple small cysts in the cerebellum, without cerebral cortical dysplasia or white matter changes. The laminin alpha(2) chain (6q2), Fukuyama type congenital muscular dystrophy (9q31-q33) and muscle-eye-brain disease (1p32-p34) loci were all excluded by linkage analysis. We suggest that this case represents a new entity in the nosology of congenital muscular dystrophy.

Central Nervous System Cysts↗
PubMed2000

Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism.

Mulibrey nanism (for muscle-liver-brain-eye nanism, MUL; MIM 253250) is an autosomal recessive disorder that involves several tissues of mesodermal origin, implying a defect in a highly pleiotropic gene. Characteristic features include severe growth failure of prenatal onset and constrictive pericardium with consequent hepatomegaly. In addition, muscle hypotonia, J-shaped sella turcica, yellowish dots in the ocular fundi, typical dysmorphic features and hypoplasia of various endocrine glands causing hormonal deficiency are common. About 4% of MUL patients develop Wilms' tumour. MUL is enriched in the Finnish population, but is rare elsewhere. We previously assigned MUL to chromosome 17q22-q23 and constructed a physical contig over the critical MUL region. The region has now been further refined by haplotype analysis and new positional candidate genes have been localized. We identified a gene with four independent MUL-associated mutations that all cause a frameshift and predict a truncated protein. MUL is ubiquitously expressed and encodes a new member of the RING-B-box-Coiled-coil (RBCC) family of zinc-finger proteins, whose members are involved in diverse cellular functions such as developmental patterning and oncogenesis.

Alternative Splicing↗
PubMed2000

Positional cloning and characterisation of the human DLGAP2 gene and its exclusion in progressive epilepsy with mental retardation.

In search of the gene for progressive epilepsy with mental retardation (EPMR) we identified DLGAP2, the human homolog of the gene encoding the rat PSD-95/SAP90-associated protein-2 (Dlgap2). We extended the transcript in both the 5' and 3' directions and characterised the genomic structure of the approximately 10 kb gene. Sequence comparisons of human DLGAP2 cDNA sequences obtained from human testis and brain cDNA libraries with homologous rat genes suggest alternative splicing in the 5' end of the gene. The 5' coding sequence of the testis cDNA is complete, whereas based on homology with the rat gene 103 bp of coding sequence may still be missing in the 5' end of the DLGAP2 brain transcript. DLGAP2 was excluded as the gene responsible for EPMR.

Base Sequence↗
PubMed2000

Seizures induce widespread upregulation of cystatin B, the gene mutated in progressive myoclonus epilepsy, in rat forebrain neurons.

Loss of function mutations in the gene encoding the cysteine protease inhibitor, cystatin B (CSTB), are responsible for the primary defect in human progressive myoclonus epilepsy (EPM1). CSTB inhibits the cathepsins B, H, L and S by tight reversible binding, but little is known regarding its localization and physiological function in the brain and the relation between the depletion of the CSTB protein and the clinical symptoms in EPM1. We have analysed the expression of mRNA and protein for CSTB in the adult rat brain using in situ hybridization and immunocytochemistry. In the control brains, the CSTB gene was differentially expressed with the highest levels in the hippocampal formation and reticular thalamic nucleus, and moderate levels in amygdala, thalamus, hypothalamus and cortical areas. Detectable levels of CSTB were found in virtually all forebrain neurons but not in glial cells. Following 40 rapidly recurring seizures evoked by hippocampal kindling stimulations, CSTB mRNA expression showed marked bilateral increases in the dentate granule cell layer, CA1 and CA4 pyramidal layers, amygdala, and piriform and parietal cortices. Maximum levels were detected at 6 or 24 h, and expression had reached control values at 1 week post-seizures. The changes of mRNA expression were accompanied by transient elevations (at 6-24 h) of CSTB protein in the same brain areas. These findings demonstrate that seizure activity leads to rapid and widespread increases of the synthesis of CSTB in forebrain neurons. We propose that the upregulation of CSTB following seizures may counteract apoptosis by binding cysteine proteases.

Animals↗
PubMed2000

Genetics of the epilepsies.

Molecular genetic analysis of mendelian epilepsies in humans and mice has revealed a diversity of underlying genes in symptomatic epilepsies associated with disordered brain development and neuronal survival. In contrast, the idiopathic mendelian epilepsies have emerged as a new category of channelopathies. New epilepsy loci have been mapped and one new epilepsy gene isolated. Functional analysis of epilepsy genes is providing new insights into the pathways that lead from mutant gene to hyperexcitable neurones. The major challenge for the future is the analysis of genetic epilepsies with complex inheritance.

Animals↗
PubMed2000

Two translocations of chromosome 15q associated with dyslexia.

Developmental dyslexia is characterised by difficulties in learning to read. As reading is a complex cognitive process, multiple genes are expected to contribute to the pathogenesis of dyslexia. The genetics of dyslexia has been a target of molecular studies during recent years, but so far no genes have been identified. However, a locus for dyslexia on chromosome 15q21 (DYX1) has been established in previous linkage studies. We have identified two families with balanced translocations involving the 15q21-q22 region. In one family, the translocation segregates with specific dyslexia in three family members. In the other family, the translocation is associated with dyslexia in one family member. We have performed fluorescence in situ hybridisation (FISH) studies to refine the position of the putative dyslexia locus further. Our results indicate that both translocation breakpoints on 15q map within an interval of approximately 6-8 Mb between markers D15S143 and D15S1029, further supporting the presence of a locus for specific dyslexia on 15q21.

Adolescent↗