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Biomedical subjects

A Gal

Publications and source records attributed to A Gal.

At least 163 records · Page 9Linked to original sources
PubMed1993

Ocular findings in a family with autosomal dominant retinitis pigmentosa and a frameshift mutation altering the carboxyl terminal sequence of rhodopsin.

A family is described in which an 8 base pair deletion (nucleotides 5252-5259, codons 341-343) of the rhodopsin gene cosegregates with autosomal dominant retinitis pigmentosa (adRP). The deletion results in a shift in the reading frame, causing a rhodopsin molecule extended by one residue and substantially altered at the carboxyl terminus. Phenotypic expression is relatively mild. In affected members, night blindness did not occur before the age of 16, and late onset of visual field loss was consistently reported. Even older individuals (59 and 76 years) had preserved central islands in the visual field; a younger female patient had normal visual fields until the age of 34. ERG and psychophysical tests showed well preserved cone function at stages of virtually abolished rod function. Phenotypic differences and similarities between this form of adRP and others associated with mutations at the carboxyl terminus of the rhodopsin molecule are discussed. The cause of RP by mutations in this region remains to be clarified.

Adult↗
PubMed1993

[Molecular genetic diagnosis of Wiskott-Aldrich syndrome].

BACKGROUND/AIMS: Wiskott-Aldrich syndrome is a severe X-linked recessive disorder of the hematopoietic system. The gene locus for Wiskott-Aldrich syndrome was mapped on the proximal short arm of the X chromosome by demonstrating close linkage to the loci DXS255 and TIMP. Carriers for Wiskott-Aldrich syndrome are asymptomatic and, hence, can not be identified clinically. METHODS: For a better estimate of the carrier risk of female family members, an extended molecular genetic analysis has been carried out on two kindreds with Wiskott-Aldrich syndrome: We followed the allele segregation at the two marker loci mentioned above known to be closely linked to the disease locus (indirect genotype diagnostics); in addition, we determined the pattern of X-inactivation by analyzing the methylation status of the two X chromosomes. RESULTS: We show that carriers for Wiskott-Aldrich syndrome can reliably be identified by the combination of segregation and X chromosome inactivation studies. Helpful information can be obtained by such studies in sporadic cases, too, or in families, in which--due to the early death--no surviving affected males are available for an DNA study. CONCLUSION: Indirect genotype analysis combined with the study of X-inactivation pattern is a valuable diagnostic tool for genetic counselling of families with Wiskott-Aldrich syndrome.

Adult↗
PubMed1992

The redox-controlled light-harvesting chlorophyll a/b protein kinase. Deactivation by substituted quinones.

The deactivation of the redox-controlled light-harvesting chlorophyll a/b protein kinase of Acetabularia acetabulum and pea thylakoids was studied. Substituted benzoquinone, naphthoquinone, and anthraquinone analogs including mono-, di-, and trihalogenated and/or alkylated quinones, which are known to inhibit the cytochrome b6/f activity, deactivate the kinase in the dark, and prevent its activation in the light. Analogs halogenated at positions 2- or 3- are the most effective deactivators. Increasing the size of the alkyl side chain and/or the number of rings lowers the deactivation effect. The activated state of the pea kinase decays with a t1/2 of 15 min, while the Acetabularia enzyme retains its active state for at least 2 h. The midpoint potential for Acetabularia kinase activity in the dark is 120 +/- 10 mV and is compatible with the involvement of plastoquinone in the kinase activation via reduction of the cytochrome complex. Deactivation of kinase by the analogs inhibiting cytochrome b6/f complex activity and the kinase copurification with the cytochrome b6/f fraction obtained from the Acetabularia thylakoid further support this conclusion. These results indicate that the process of kinase activation/deactivation includes the binding of plastoquinol or quinone analogs by the cytochrome complex and its interaction with the kinase. We propose that the latter process may constitute the rate-limiting step controlling the kinase activation/deactivation kinetics.

Acetabularia↗
PubMed1992

Deletion of the Hunter gene and both DXS466 and DXS304 in a patient with mucopolysaccharidosis type II.

Hunter syndrome is an X-linked mucopolysaccharidosis due to deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). A cDNA clone containing the entire coding region of the human IDS gene, mapped in Xq28, has been used as molecular probe to study a patient with Hunter syndrome. A submicroscopic deletion has been detected that spans the IDS gene as well as DXS466 and DXS304, 2 loci mapped probably not more than 900 kb from the IDS locus. A detailed clinical description of the patient is provided and his phenotype is compared to that of other patients with IDS deletion described recently. By following the segregation of a restriction fragment length polymorphism at the IDS locus in the patient's family, our data suggest that the deletion occurred in the germ cells of the patient's grandfather.

Blotting, Southern↗
PubMed1992

Phosphorylation of cytochrome b6 by the LHC II kinase associated with the cytochrome complex.

The cytochrome b6 polypeptide present in cytochrome b6/f preparations from spinach thylakoids is phosphorylated concomitantly with the autophosphorylation of the 64 kDa polypeptide identified as the redox-controlled LHCII kinase. The N-terminal sequence of the 64 kDa kinase and sequence analysis of cytochrome b6 indicate the existence of putative phosphorylation sites in both proteins.

Amino Acid Sequence↗
PubMed1992

Clinical and ERG data in a family with autosomal dominant RP and Pro-347-Arg mutation in the rhodopsin gene.

In a family with autosomal dominant retinitis pigmentosa, documented over six generations, a previously undescribed point mutation in the rhodopsin gene could be identified. The mutation found in the six affected members examined but in none of the controls, including healthy members of the family, was a point mutation in codon 347 predicting a substitution of the amino acid arginine for proline, designated Pro-347-Arg. Six affected members from two generations were examined clinically and with ganzfeld rod and cone electroretinography. The cone and, more dramatically, the rod electroretinograms were reduced to residual b-wave amplitudes or were non-detectable as early as ages 18 to 22 years. The Pro-347-Arg mutation resulted in a subjectively and clinically homogeneous phenotype: early onset of night blindness before age 11, relatively preserved usable visual fields until about age 30, blindness at ages 40 to 60, and change from an initial apparently sine pigmento to a hyperpigmented and atrophic fundus picture between 30 and 50 years of age.

Adolescent↗
PubMed1992

Deletions in exon 5 of the human rhodopsin gene causing a shift in the reading frame and autosomal dominant retinitis pigmentosa.

By screening patients with autosomal dominant retinitis pigmentosa for mutations in the rhodopsin gene, two deletions (8 bp and 1 bp) have been identified in exon 5; these deletions cause a shift in the reading frame. The predicted proteins should be radically altered with translation continuing past the normal stop signal and resulting in a rhodopsin molecule that is, respectively, 1 and 10 amino acids longer. The clinical phenotype of the patients is described and is compared with that associated with other mutations in the same region of the gene.

Adult↗
PubMed1992

Evidence for nonallelic genetic heterogeneity in autosomal recessive retinitis pigmentosa.

Recent evidence suggesting the involvement of mutant rhodopsin proteins in the pathogenesis of autosomal recessive retinitis pigmentosa has prompted us to investigate whether this form of the disease shows non-allelic genetic heterogeneity, as has previously been shown to be the case in autosomal dominant retinitis pigmentosa. The availability of a unique inbred Dutch pedigree has enabled us to address this question. We have used an intragenic polymorphism to exclude the possibility that a mutation in the rhodopsin gene is responsible for the disease in this patient population. These data provide evidence for the involvement of at least two loci in autosomal recessively inherited retinitis pigmentosa.

Base Sequence↗
PubMed1992

Norrie disease is caused by mutations in an extracellular protein resembling C-terminal globular domain of mucins.

A candidate gene for Norrie disease, an X-linked disorder characterized by blindness, deafness and mental disturbances, was recently isolated and found to contain microdeletions in numerous patients. No strong homologies were identified. By studying the number and spacing of cysteine residues, we now detect homologies between the Norrie gene product and a C-terminal domain which is common to a group of proteins including mucins. Three newly-characterized missense mutations, replacing evolutionarily conserved cysteines or creating new cysteine codons, emphasize the functional importance of these sites. These findings and the clinical features of this disorder suggest a possible role for the Norrie gene in neuroectodermal cell-cell interaction.

Adult↗
PubMed1992

Mutation analysis of the iduronate-2-sulfatase gene in patients with mucopolysaccharidosis type II (Hunter syndrome).

Iduronate-2-sulfatase (IDS) cDNA from fibroblasts of nine patients with Hunter syndrome (mucopolysaccharidosis type II) was screened for mutations using single strand conformation polymorphism analysis. Direct sequencing revealed a number of different mutations including missense or nonsense point mutations, deletions of one, two, or 60 base pairs, and a 22 base pair-insertion. Mutations of these types probably account for most IDS gene defects as only about 20% of Hunter patients have a complete deletion or gross structural alteration of their IDS gene. Thus the broad clinical variability amongst the Hunter patients may be due to the extensive genetic heterogeneity seen. The relationship between genotype and clinical phenotype is analysed in 12 Hunter patients.

Adolescent↗
PubMed1992

Mutations in the candidate gene for Norrie disease.

Recently, we and others have isolated a candidate gene for X linked Norrie disease (ND) which was found to be deleted or disrupted in several patients. As a prerequisite for the identification of point mutations in the ND gene we have established the exon-intron structure of this gene. In 17 unrelated patients and 15 controls, PCR products derived from the promoter region, exons 1 and 2 as well as the coding part of exon 3 were analysed with the single strand conformation polymorphism (SSCP) technique. In 12 patients altered PCR fragments were detected which were studied in detail by direct sequencing. Eleven different mutations were found, and all but one are likely to give rise to significant structural changes in the predicted protein. These findings, and the absence of functionally relevant base changes in healthy controls, emphasize the causal role of this candidate gene in Norrie disease and pave the way for reliable diagnosis and carrier detection.

Base Sequence↗
PubMed1992

Ring Y chromosome: cytogenetic and molecular characterization.

A female patient with Turner syndrome and the karyotype mos45,X/46,X,r(Y)/46,XY is described. Physical mapping of the ring chromosome by Y-specific single-copy and moderately repeated DNA sequences as molecular probes showed that, in addition to the heterochromatic part of Yq, a considerable portion of the Yp has also been lost in the course of the rearrangement. Thus, molecular findings provide independent support that this structurally abnormal sex chromosome is a ring Y and agree with the generally accepted model of ring formation requiring breaks in both chromosome arms. Clinical consequences of Y chromosome mosaicism in patients with Turner syndrome are discussed.

Blotting, Southern↗
PubMed1992

Carrier detection in X-linked ocular albinism of the Nettleship-Falls type by DNA analysis.

X-linked ocular albinism (XOA) is characterized by anomalies of the eyes and hypopigmentation or absence of pigment in skin, hair and eyes due to a hereditary inborn error of metabolism affecting the pigment cells. The gene of XOA of the Nettleship-Falls type (OA1) has been mapped to Xp22.3, and several closely linked RFLP loci have been identified. Linkage analysis and deletion mapping have established the marker gene order Xpter-STS-DX237-(OA1,DXS143,DXS85)-DXS1 6-DXS43-Xcen. Although the position of OA1 has yet not been fully resolved, we report on the first carrier detections in OXA of the Nettleship-Falls type by DNA analysis using markers which unquestionably flank OA1.

Albinism, Ocular↗
PubMed1992

The autosomal dominant familial exudative vitreoretinopathy locus maps on 11q and is closely linked to D11S533.

Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is a hereditary disorder characterized by the incomplete vascularization of the peripheral retina. The primary biochemical defect in adFEVR is unknown. The adFEVR locus has tentatively been assigned to 11q by linkage studies. We report the results of an extended multipoint linkage analysis of two families with adFEVR by using five markers (INT2, D11S533, D11S527, D11S35, and CD3D) from 11q13-q23. Pairwise linkage data obtained in the two families were rather similar and hence have not provided evidence for genetic heterogeneity. The highest complied two-point lod score (3.67, at a recombination fraction of .07) was obtained for the disease locus versus D11S533. Multipoint analyses showed that the adFEVR locus maps most likely, with a maximum location score of over 20, between D11S533/D11S527 and D11S35, at recombination rates of .147 and .104, respectively. Close linkage without recombination (maximum lod score 11.26) has been found between D11S533 and D11S527.

Chromosome Mapping↗
PubMed1992

Diffuse loss of rod function in autosomal dominant retinitis pigmentosa with pro-347-leu mutation of rhodopsin.

There is considerable variety among the clinical features of autosomal dominant retinitis pigmentosa (ADRP). This is probably at least in part due to genetic heterogeneity. Recently, various mutations of the rhodopsin gene have been detected in some ADRP families. We report on six patients from two families with ADRP who were investigated by means of psychophysical and electrophysiological methods. All displayed the same rhodopsin gene mutation at codon 347, which exchanges the amino acid proline for leucine (pro-347-leu). The patients had early-onset night blindness and impaired side vision as of the end of their second life decade. They produced monophasic dark-adaptation curves, showing a lack of rod function and elevated cone thresholds. Dark-adapted two-color threshold perimetry using 500- and 650-nm stimuli revealed a diffuse loss of rod function and centrally preserved cone function. The electroretinogram was nonrecordable at the age of about 30 years. A certain variability of visual function loss was noted among patients in the overall severe course of the disease, but the clinical findings of this genotype corresponded to type 1 ADRP of Massof and Finkelstein in all cases.

Adult↗