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Cotton, R. G. H.; Kazazian, Haig H.
1996 Human Mutation
doi: 10.1002/humu.1380080304pmid: N/A
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Cotton, R. G. H.; Kazazian, Haig H.
doi: 10.1002/humu.1380080304pmid: N/A
Beutler, Ernest; Gelbart, Terri
doi: 10.1002/(sici)1098-1004(1996)8:3<207::aid-humu2>3.0.co;2-6pmid: 8889578
Gaucher disease is the most common glycolipid storage disorder, characterized by storage of the glycolipid, glucocerebroside in the liver, spleen, and marrow. The most prevalent form of Gaucher disease is designated type I (MIM 230800). Patients with type I disease may have hepatomegaly, splenomegaly, bone lesions, and less commonly, lung disease, but are free of neurological involvement. Types II (MIM 230900) and III (MIM 2310000), the acute infantile and juvenile forms, respectively, of Gaucher disease, are characterized by the fact that the central nervous system is affected. © 1996 Wiley‐Liss, Inc.
Merante, F.; Myint, T.; Tein, I.; Benson, L.; Robinson, B.H.
doi: 10.1002/(sici)1098-1004(1996)8:3<216::aid-humu4>3.0.co;2-7pmid: 8889580
A third point mutation in the mitochondrial tRNAIle gene associated with hypertrophic cardiomyopathy and respiratory chain dysfunction in heart is reported. An A‐to‐G transition at nucleotide position 4295 was shown to be highly evolutionarily conserved, never present in control individuals, and to segregate with the disease. A PCR‐based diagnostic test and endomyocardial biopsies were used to detect both the biochemical deficiency and the level of heteroplasmy in heart. The implications of this new mitochondrial DNA point mutation are discussed. © 1996 Wiley‐Liss, Inc.
Katz, Fay; Hinshelwood, Steve; Rutland, Paul; Jones, Alison; Kinnon, Christine; Morgan, Gareth
doi: 10.1002/(sici)1098-1004(1996)8:3<223::aid-humu5>3.0.co;2-apmid: 8889581
Mutations in the gene encoding CD40 ligand have been shown to be the cause of X‐linked hypogammaglobulinemia with hyper IgM (HIGM1). We have used the technique of single strand conformational polymorphism (SSCP) analysis to screen for mutations in this gene in affected boys from nineteen unrelated families. Sixteen novel mutations were identified in patients, comprising six patients with single base substitutions, two patients with single base insertions, six patients with deletions ranging from one to seven bases and two patients with large deletions at the 5′ end of the gene. These mutations were distributed throughout the gene. SSCP band shifts and/or alterations in restriction enzyme digestion sites could be used for unambiguous determination of carrier status in at‐risk female relatives of most of the affected boys and, in some cases, prenatal diagnosis also can be offered. © 1996 Wiley‐Liss, Inc.
Hughes, David; Wallace, Andrew; Taylor, Joanne; Tassabehji, May; McMahon, Roger; Hill, Alison; Nevin, Norman; Graham, Colin
doi: 10.1002/(sici)1098-1004(1996)8:3<229::aid-humu6>3.0.co;2-4pmid: 8889582
The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene contains three highly informative microsatellites: IVS8CA, IVS17bTA, and IVS17bCA. Their analysis improves prenatal / carrier diagnosis and generates haplotypes from CF chromosomes that are strongly associated with specific mutations. Microsatellite haplotypes were defined for 75 CFTR mutations carried on 437 CF chromosomes (220 for ΔF508, 217 for other mutations) from Northern Ireland and three English regions: the North‐West, East Anglia, and the South. Fluorescently labelled microsatellites were amplified in a triplex PCR reaction and typed using an ABI 373A fluorescent fragment analyser. These mutations cover all the common and most of the rare CF defects found in the UK, and their corresponding haplotypes and geographic region are tabulated here. Ancient mutations, ΔF508, G542X, N1303K, were associated with several related haplotypes due to slippage during replication, whereas other common mutations were associated with the one respective haplotype (e.g., G551D and R560T with 16‐7‐17, R117H with 16‐30‐13, 621 + 1G>T with 21‐31‐13, 3659delC with 16‐35‐13). This simple, fast, and automated method for fluorescent typing of these haplotypes will help to direct mutation screening for uncharacterised CF chromosomes. © 1996 Wiley‐Liss, Inc.
Knappskog, Per M.; Eiken, Hans Geir; Martínez, Aurora; Bruland, Ove; Apold, Jaran; Flatmark, Torgeir
doi: 10.1002/(sici)1098-1004(1996)8:3<236::aid-humu7>3.0.co;2-7pmid: 8889583
We have used three complementary in vitro systems to express the human phenylalanine hydroxylase (PAH) gene at high levels. Recombinant PAH was expressed in Escherichia coli (as a fusion protein), in human kidney cells and in a cell‐free in vitro transcription‐translation system. These systems were used to characterize a novel kinetic variant form (D143G) of the enzyme. The recombinant D143G mutant enzyme had the same physicochemical properties as the wild‐type PAH and was stable when expressed in eukaryotic cells. Enzyme activity studies of the D143G mutant enzyme, produced in the three expression systems, revealed a kinetic variant form with reduced affinity for L‐Phe (about 2.4‐fold increase in the S0.5 value) as well as reduced affinity for tetrahydrobiopterin (BH4) (about 2‐fold increase in the apparent Km). At standard assay conditions (1 mM L‐Phe, 75 μM BH4) the residual activity of the mutant enzyme was high and variable (52%, 33%, and 102%) when analysed in the three different systems. The high residual activities of the mutant enzyme obtained at these conditions were not in agreement with the classical PKU phenotype found in a patient compound heterozygous for the termination mutation G272X and the novel D143G mutation. However, when the D143G mutant enzyme was assayed at lower concentrations of L‐Phe (100–300 μM) and BH4 (10 μM) the residual activities were compatible with severely reduced hydroxylation of L‐Phe and the classical PKU phenotype. © 1996 Wiley‐Liss, Inc.
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