Two patients with Hermansky Pudlak syndrome type 2 and novel mutations in AP3B1.
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Identification of a platelet dense granule membrane protein that is deficient in a patient with the Hermansky-Pudlak syndrome.
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Monoclonal antibodies were raised after injecting mice with isolated human dense granules. Several of these monoclonals were found to recognize a 40-Kd dense granule membrane protein. Western blot and immunofluorescent analysis confirmed the dense-granule specificity. After thrombin activation, the protein was found in patches on the external platelet membrane. By Western blot and slot blot analysis, the protein was found to be markedly deficient in a patient with the Hermansky-Pudlak syndrome. Studies of neutrophils and endothelial cells show the presence of immunologically related granule-membrane protein(s). Western blots using four anti-synaptophysin antibodies and three antibodies to the platelet 40-Kd protein suggest that the protein may share some homology with, but is not identical to, the synaptosomal membrane protein synaptophysin. (+info)
A comprehensive analysis reveals mutational spectra and common alleles in Chinese patients with oculocutaneous albinism.
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Tilted disc syndrome in Congolese patients.
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Microarray analysis of iris gene expression in mice with mutations influencing pigmentation.
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Spectrum of candidate gene mutations associated with Indian familial oculocutaneous and ocular albinism.
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PURPOSE: Albinism is a group of genetic disorders, showing a broad spectrum of different phenotypes. The purpose of this study was to screen known candidate genes for oculocutaneous albinism (OCA) and ocular albinism (OA) mutations in Indian patients. METHODS: Blood samples were collected from 23 probands and 13 affected family members from 23 genetically unrelated Indian families (22 diagnosed as OCA and 1 diagnosed as OA) and analyzed by bidirectional DNA sequencing of the classic OCA genes--tyrosinase (TYR, or oculocutaneous albinism IA), pink eyed dilution (P; or oculocutaneous albinism II (OCA2]), tyrosinase-related protein 1 (TYRP1), solute carrier family 45, member 2 (SLC45A2; or membrane-associated transporter protein [MATP])--and the OA1 gene, G protein-coupled receptor 143 (GPR143). RESULTS: Three missense mutations, c. 715 C>T (R239W), c. 896 G>A (R299H), c.1255 G>A (G419R), and one termination c. 832 C>T (R278X), were identified in TYR, as well as one novel mutation, c.1453 G>A (G485R) in P. One novel single nucleotide polymorphism (SNP) was identified in both TYR and P; few reported SNPs were identified. The G>A base substitution caused relatively conservative amino acid changes, which altered glycine to arginine residues within the topological domain. The novel OCA2 mutation was not present in 100 control samples. This study identified two probands carrying mutations alone, 16 probands carrying SNPs alone, 4 probands carrying both mutations and SNPs and only one proband carrying neither mutations nor SNPs. CONCLUSIONS: Although sequence analysis was performed with all five candidate genes, only four (17.39%) of the 23 probands showed mutations in TYR and 2 probands (8.69%) showed an unreported novel mutation in P. Genetic counseling for phenotypical diagnosis and genetic mutation screening of these genes will help to minimize the incidence of OCA and OA in future generations. (+info)
Molecular and clinical characterization of albinism in a large cohort of Italian patients.
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Molecular basis of tyrosinase-negative oculocutaneous albinism. A single base mutation in the tyrosinase gene causing arginine to glutamine substitution at position 59.
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Tyrosinase-negative oculocutaneous albinism (OCA) is one of classical inborn errors of metabolism, characterized by a complete lack of melanin pigments in the eyes and skin. We have isolated and characterized the tyrosinase gene of one child (F. S.) affected with tyrosinase-negative OCA. Sequence analysis reveals a single-base mutation in the exon 1 (a G to A transition at nucleotide residue 312), causing the Arg (CGG) to Gln (CAG) substitution at position 59. This base change eliminates one MspI site and creates a new BstNI site in the patient's exon 1, which is invaluable for screening other OCA patients and heterozygote carriers for this mutation. We are thus able to confirm that the patient F. S. is homozygous for this OCA allele. The family members of the patient F. S. are phenotypically normal, but are shown to be heterozygote carriers. Transfection of the mutant gene fails to give rise to detectable tyrosinase activity in transient expression assays, suggesting that the mutation affects the stability or the catalytic activity of the enzyme. We therefore propose that the albino phenotype of the patient F. S. is a consequence of the Arg to Gln substitution at position 59 caused by a point mutation in the tyrosinase gene. (+info)