Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003635 (apraxia)
 2,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gaucher disease is an inherited sphingolipidosis resulting from deleterious mutations in the glucocerebrosidase gene. Through direct sequence analysis of genomic DNA from whole blood, fibroblast cultures, and formalin-fixed archival tissue samples, we have identified a rare homozygous C > T transition at cDNA nucleotide 481 of the glucocerebrosidase gene that results in a proline to serine amino acid substitution (p.P122S) in an aboriginal family of Cree descent in northern Alberta, Canada. A 13-month-old boy (JB) presented with severe visceral Gaucher disease and was treated with enzyme replacement. Currently, at 11 years he is developmentally delayed, with oculomotor apraxia. A cousin (MS) had previously died at age 7 from complications of severe Gaucher disease, before enzyme replacement therapy was available. She was also developmentally delayed. Heterologous expression of this allele using a baculovirus expression system revealed 19.2% of normal enzyme activity on the artificial substrate 4-methylumbelliferyl beta-d-glucopyranoside (4MUGP). Genotype/phenotype correlation is complicated by incomplete clinical details, enzyme replacement therapy, and the difficulty in excluding other genetic and environmental causes of developmental delay. However the development of oculomotor apraxia in JB suggests a Type 3 Gaucher phenotype. The only previous report of this mutation was also from a member of the Cree Nation, who has had a rather similar clinical course. A protocol is described for the isolation of genomic DNA from formalin-fixed bone marrow aspirate archival specimens obtained from the deceased for subsequent PCR-based sequence analysis and mutation detection. This technique will be applicable to the screening of this and other populations for the frequency of known Gaucher mutations where traditional DNA sources are unavailable.
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PMID:Heterologous expression and characterization of a rare Gaucher disease mutation (c.481C > T) from a Canadian aboriginal population using archival tissue samples. 1170 65

Early onset familial Alzheimer disease (FAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. We reported previously a variant form of FAD, due to deletion of exon 9 of PSEN1, with spastic paralysis and rigidity. We describe a novel PSEN1 mutation in a family of Japanese origin with six affected individuals of both genders in two generations. The disease is characterized by presenile dementia, which is preceded by spastic paraparesis and apraxia. This mutation, which is predicted to cause a missense substitution of serine for glycine, occurred at codon 266 in exon 8 of PSEN1. The mutation was not found in 200 controls and 200 sporadic AD patients. On this basis alone, it seems this mutation is pathogenic. Our findings provide a new clue to the etiology of the familial early onset dementia.
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PMID:Molecular evidence of presenilin 1 mutation in familial early onset dementia. 1192 Aug 51

Ten new patients with ataxia telangiectasia-like disorder (ATLD) from three unrelated Saudi Arabian families have been identified aged 5-37 representing the largest cohort of ATLD patients ever identified. They presented with an early-onset, slowly progressive, ataxia plus ocular apraxia phenotype with an absence of tumor development, even in the oldest patient. Extra-neurological features such as telangiectasia, raised alpha-fetoprotein and reduced immunoglobulin levels were absent. No translocations were found in the two investigated patients, and the presence of microcephaly was noted in four out of eight ascertained patients. All patients are homozygous for a novel missense mutation (630G-->C, W210C) of the MRE11 gene. The cellular consequences of this amino acid change, localized in the nuclease domain of the Mre11 protein, have been determined in fibroblast cultures established from two individuals. They showed high constitutive levels of Mre11 and Rad50 proteins compared with cells from normal individuals but a very low level of the Nbs1 protein. After exposure to ionizing radiation, a dose-dependent defect in ataxia telangiectasia mutated (ATM)-serine 1981, p53-serine 15 and Chk2 phosphorylation, and p53 stabilization were noted, together with a failure to form Mre11 foci and enhanced radiation sensitivity. Formation of gammaH2AX foci was similar to that seen in normal fibroblasts under the experimental conditions examined. These results emphasize the importance of functional interactions among the three proteins of the Mre11-Rad50-Nbs1 complex and lend support to a role of this complex as a sensor of DNA double-strand breaks, acting upstream of ATM.
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PMID:Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder. 1557 63