ERGIC-53 gene structure and mutation analysis in 19 combined factors V and VIII deficiency families.
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Combined factors V and VIII deficiency is an autosomal recessive bleeding disorder associated with plasma levels of coagulation factors V and VIII approximately 5% to 30% of normal. The disease gene was recently identified as the endoplasmic reticulum-Golgi intermediate compartment protein ERGIC-53 by positional cloning, with the detection of two founder mutations in 10 Jewish families. To identify mutations in additional families, the structure of the ERGIC-53 gene was determined by genomic polymerase chain reaction (PCR) and sequence analysis of bacterial artificial chromosome clones containing the ERGIC-53 gene. Nineteen additional families were analyzed by direct sequence analysis of the entire coding region and the intron/exon junctions. Seven novel mutations were identified in 10 families, with one additional family found to harbor one of the two previously described mutations. All of the identified mutations would be predicted to result in complete absence of functional ERGIC-53 protein. In 8 of 19 families, no mutation was identified. Genotyping data indicate that at least two of these families are not linked to the ERGIC-53 locus. Taken together, these results suggest that a significant subset of combined factors V and VIII deficiency is due to mutation in one or more additional genes. (+info)
Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes.
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The complement protein C4, encoded by two genes (C4A and C4B) on chromosome 6p, is the most polymorphic among the MHC III gene products. We investigated the molecular basis of C4 deficiency in a Finnish woman with systemic lupus erythematosus. C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected. This defect in C4 expression was specific in that synthesis of two other complement proteins was normal. Analysis of genomic DNA showed that the proposita had both deleted and nonexpressed C4 genes. Each of her nonexpressed genes, a C4A null gene inherited from the mother, a C4A null gene, and a C4B null gene inherited from the father, all contained an identical 2-bp insertion (TC) after nucleotide 5880 in exon 29, providing the first confirmatory proof of the C4B pseudogene. This mutation has been previously found only in C4A null genes. Although the exon 29/30 junction is spliced accurately, this frameshift mutation generates a premature stop at codon 3 in exon 30. These truncated C4A and C4B gene products were confirmed through RT-PCR and sequence analysis. Among the possible genetic mechanisms that produce identical mutations is both genes, the most likely is a mutation in C4A followed by a gene conversion to generate the mutated C4B allele. (+info)
The orthopaedic aspects of multiple epiphyseal dysplasia.
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Five cases of multiple epiphyseal dysplasia (MED) were treated from 1985-1996 at the Orthopaedics and Trauma Department of SSK Izmir Educational Hospital. Four patients were female and one was male. The pedigrees of the first two female patients had the same features of inter-related marriages. The patients have been followed up for 5.5-11 years (average of 7.5 years). Surgical operations were mostly required in the lower limbs. Problems in the hips required adductor myotomy, the Soutter procedure, total hip replacement, and pertrochanteric extension osteotomy. Management of the knees required supracondylar shortening and extension osteotomy of the femur, high tibial extension osteotomy, debridement of the knee joint with removal of osteophytes, ogleotomy of the patellar lengthening of the knee flexors and posterior capsulotomy. Interphalangeal arthrodesis for hammer toes, extension osteotomy of the head of the first metatarsals, and Kellers operation were carried out in the foot. In the upper limb decompression and anterior transposition of the ulnar nerve, debridement of the elbow joint, extension and valgus osteotomy of the distal radius, and extension osteotomy of the head of the first metacarpal were required. (+info)
Novel mutations in Rsk-2, the gene for Coffin-Lowry syndrome (CLS).
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Coffin-Lowry syndrome (CLS) is an X-linked disorder characterized by facial dysmorphism, digit abnormalities and severe psychomotor retardation. CLS had previously been mapped to Xp22.2. Recently, mutations in the ribosomal S6 kinase (Rsk-2) gene were shown to be associated with CLS. We have tested five unrelated individuals with CLS for mutations in nine exons of Rsk-2 using Single Strand Conformation Polymorphism (SSCP) analysis. Two patients had the same missense mutation (C340T), which causes an arginine to tryptophan change (R114W). This mutation falls just outside the N-terminal ATP-binding site in a highly conserved region of the protein and may lead to structural changes since tryptophan has an aromatic side chain whereas arginine is a 5 carbon basic amino acid. The third patient also had a missense mutation (G2186A) resulting in an arginine to glutamine change (R729Q). The fourth patient had a 2bp deletion (AG) of bases 451 and 452. This creates a frameshift that results in a stop codon 25 amino acids downstream, thereby producing a truncated protein. This deletion also falls within the highly conserved amino-catalytic domain of the protein. The fifth patient has a nonsense mutation (C2065T) which results in a premature stop codon, thereby producing a truncated protein. These mutations further confirm Rsk-2 as the gene involved in CLS and may help in understanding the structure and function of the protein. (+info)
Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene.
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We studied a large Dutch family with maternally inherited, progressive, sensorineural hearing loss in 27 patients. Only in a single family member was the hearing loss accompanied by neurological symptoms including ataxia and dysarthria. DNA analysis of the mitochondrial genome revealed the insertion of a C at nucleotide position 7472 in the tRNASer(UCN) gene (7472insC mutation). We determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leucocyte heteroplasmy. The 7472insC mutation was previously identified in a smaller family from Sicily with sensorineural hearing loss in 9 family members, six of them also presenting neurologically with ataxia and myoclonus. The presence of the 7472insC mutation in two different pedigrees strongly supports its pathogenicity. However, the interfamilial difference in penetrance of the neurologic abnormalities is most likely to be strongly influenced by secondary factors different from the 7472insC mutation, as heteroplasmy or age of the patients were similar in both families. This mutation should therefore be analysed in families with maternally inherited hearing loss, irrespective of whether the hearing loss is non-syndromic or accompanied by neurologic abnormalities. (+info)
Lamellar ichthyosis: further narrowing, physical and expression mapping of the chromosome 2 candidate locus.
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Lamellar ichthyosis (LI) is an autosomal recessive genodermatosis which has been shown to be both clinically and genetically heterogeneous. Keratinocyte transglutaminase (or transglutaminase 1: TGM1) has been demonstrated to be the disease-causing gene in some families, whilst in others, a second unidentified LI gene was mapped to chromosome 2q33-35 (ICR2B locus). In this study, we present a physical map that encompasses the ICR2B locus, including the mapping of new microsatellite markers. Based on this new map, genotyping additional families highly suggests a reduction in size of the candidate interval. The final interval is covered by a single yeast artificial chromosome (937-H-3) which is 2.2Mb in length. Fine mapping of potential candidate transcripts was also focused on this region. (+info)
Full results of the genome-wide scan which localises a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33.
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Three hundred million individuals are at risk of infection by schistosomes, and thousands die each year of severe hepatic disease. Previous studies have shown that the intensity of infection by Schistosoma mansoni in a Brazilian population is controlled by a major gene, denoted as SM1. We report here the full results of a genome-wide search that was performed on this population to localise SM1. Two hundred and forty-six microsatellites were used for the primary map, and only one region in 5q31-q33 provided significant evidence of linkage. SM1 was subsequently mapped to this region, which contains several genes encoding cytokines or cytokine receptors which are involved in protection against schistosomes. Three additional regions, 1p22.2, 7q36 and 21q22-22-qter, yielded promising, although not significant, lod-score values. These regions contain candidate genes encoding cytokines or molecules relevant to anti-schistosome immunity. (+info)
Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease.
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We have identified a novel beta amyloid precursor protein (betaAPP) mutation (V715M-betaAPP770) that cosegregates with early-onset Alzheimer's disease (AD) in a pedigree. Unlike other familial AD-linked betaAPP mutations reported to date, overexpression of V715M-betaAPP in human HEK293 cells and murine neurons reduces total Abeta production and increases the recovery of the physiologically secreted product, APPalpha. V715M-betaAPP significantly reduces Abeta40 secretion without affecting Abeta42 production in HEK293 cells. However, a marked increase in N-terminally truncated Abeta ending at position 42 (x-42Abeta) is observed, whereas its counterpart x-40Abeta is not affected. These results suggest that, in some cases, familial AD may be associated with a reduction in the overall production of Abeta but may be caused by increased production of truncated forms of Abeta ending at the 42 position. (+info)