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R A Spritz

Publications and source records attributed to R A Spritz.

At least 37 records · Page 2Linked to original sources
PubMed1998

A gene for autosomal dominant hypohidrotic ectodermal dysplasia (EDA3) maps to chromosome 2q11-q13.

Autosomal dominant hypohidrotic ectodermal dysplasia (ADHED) is a disorder characterized by fine, slow-growing scalp and body hair, sparse eyebrows and eyelashes, decreased sweating, hypodontia, and nail anomalies. By genetic linkage analysis of a large ADHED kindred, we have mapped a gene for ADHED (EDA3) to the proximal long arm of chromosome 2 (q11-q13). Obligate recombinations localize EDA3 to an approximately 9-cM interval between D2S1321 and D2S308, with no apparent recombinations with markers D2S1343, D2S436, D2S293, D2S1894, D2S1784, D2S1890, D2S274, and CHLC.GAAT11C03.

Chromosomes, Human, Pair 2↗
PubMed1998

Linkage disequilibrium mapping of the gene for Margarita Island ectodermal dysplasia (ED4) to 11q23.

Margarita Island ectodermal dysplasia (ED4) is an autosomal recessive disorder characterized by unusual facies, dental anomalies, hypotrichosis, palmoplantar hyperkeratosis and onychodysplasia, syndactyly, and cleft lip/cleft palate. We have used an affected-only DNA-pooling strategy to carry out linkage disequilibrium mapping of the ED4 gene to 11q23. Haplotype analysis of four complex Margarita Island ED4 families localized the ED4 gene to an approximately 1-2-Mb interval spanned by just two YACs.

Chromosome Mapping↗
PubMed1997

Autosomal dominant hypohidrotic ectodermal dysplasia in a large family.

We have studied an autosomal dominant hypohidrotic ectodermal dysplasia in 38 individuals over six generations in one family. Thirty-two affected individuals in four generations are still living. Questionnaire responses were received from 21 of the affected relatives and some of the individuals were examined by one of the authors. Smooth, dry, thin skin is seen in most affected individuals. Nearly all have fine, slow-growing scalp and body hair and all have sparse eyebrows and short eyelashes. Nearly all show a decrease in sweating, with some only sweating under the arms and/or on the palms and soles. All affected individuals lacked some deciduous teeth and some permanent teeth. Some teeth are abnormally shaped. Nail abnormalities are more variable and may occur more frequently with increasing age. No other abnormalities are seen in affected individuals in this family. We reviewed 40 autosomal dominant ectodermal dysplasia syndromes. This family bears some resemblance to a family described by Jorgensen et al. [1987]; however, it appears to represent a disorder that has not been described previously.

Abnormalities, Multiple↗
PubMed1997

Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele.

The Prader-Willi syndrome (PWS) usually results from a paternal deletion of 15q11-q13 or maternal disomy for chromosome 15. Reduced pigmentation of skin, hair, and eyes is common in PWS and was suggested previously to be associated with the 15q11-q13 deletion. The P gene, located in this same region, is associated with OCA2, an autosomal recessive disorder that is the most frequent form of tyrosinase-positive oculocutaneous albinism. We studied 28 individuals with PWS and found that hemizygosity for the P gene was significantly correlated with the occurrence of hypopigmentation among PWS patients. However, we found little or no relationship between the occurrence of hypopigmentation and the polymorphism haplotype of the intact P allele. Thus, our results indicate that hypopigmentation is likely the result of deletion of the P gene in the context of PWS but do not support the linked hypothesis that hypopigmentation results from hemizygosity for variant P alleles with reduced function.

Alleles↗
PubMed1997

Loss of expression of receptor tyrosine kinase family genes PTK7 and SEK in metastatic melanoma.

Protein tyrosine kinases (PTKs) have been implicated in the development of many common human tumours including melanoma. Previously we isolated PTK gene sequences expressed in normal melanocytes. Here we examined expression of 9 of these genes in cell lines derived from defined stages of melanoma progression, by Northern blotting and in some cases immunoblotting. We also tested cells from 2 animal models of particular stages in progression, as well as uncultured biopsies of metastatic melanoma. The expression of 2 receptor kinase family members found in melanocytes, PTK7/CCK-4 and SEK/TYRO1, was decreased or lost in advanced melanomas. PTK7 mRNA was found in only 54% of melanoma cell lines and 20% of melanoma biopsies. Similarly, expression was lost in 2 advanced cell lines selected from an early melanoma line that did express PTK7 mRNA. SEK/TYRO1 expression was observed in 75% and 17% of cell lines from primary and metastastic melanomas, respectively. Conversely, mRNA for the non-receptor kinase PTK6/BRK was not detected in normal melanocytes or primary melanoma lines, but was found in 9% of metastatic melanoma cell lines.

Cell Adhesion Molecules↗
PubMed1997

Prevalent and novel mutations of the tyrosinase gene in Korean patients with tyrosinase-deficient oculocutaneous albinism.

We analyzed the tyrosinase (TYR) gene of 12 Korean patients with various types of oculocutaneous albinism (OCA). We identified five different mutations in the TYR gene in 4 patients with severe OCA and in 2 patients with mild OCA, but found no mutations in the 6 patients with mild OCA phenotypes. Among the 5 mutations, a frameshift mutation, P310insC, was detected most frequently (allele frequency = 0.5), and the other mutations were found less frequently, two of which, L288delT and IVS2-7t-->a,-10(-)-11deltt, are novel. This study may provide valuable information for the molecular diagnosis of and accurate genetic counseling for OCA1 in Koreans and perhaps other Asian groups.

Adult↗
PubMed1997

Piebaldism, Waardenburg syndrome, and related disorders of melanocyte development.

Recent years have seen the identification of a complex network of interacting genes that regulates embryonic development of melanocytes, and many different genetic disorders of melanocyte development of both humans and the laboratory mouse have now been associated with abnormalities of these regulatory genes. Disorders of melanocyte development are characterized by heterogeneous distribution of pigmentation, so-called 'white spotting,' typified by piebaldism and Waardenburg syndrome. It is now clear that these disorders of pigment cell development represent a subgroup of the neurocristopathies, involving defects of various neural crest cell lineages that include melanocytes, but also involving many other tissues derived from the neural crest.

Animals↗
PubMed1997

Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA).

Waardenburg syndrome (WS) is a clinically and genetically heterogeneous disease accounting for >2% of the congenitally deaf population. It is characterized by deafness in association with pigmentary anomalies and various defects of neural crest-derived tissues. At least four types are recognized (WS1, WS2, WS3 and WS4) on the basis of clinical and genetic criteria. Two previously described families seemed to delineate a new subtype characterized by WS2 in conjunction with ocular albinism (OA). Since mutations in the MITF gene are responsible for some instances of WS2, we screened for mutations in one of the WS2-OA families and discovered a 1 bp deletion in exon 8 of MITF. OA previously has been associated with compound heterozygosity for a mutant TYR allele and the TYR(R402Q) allele, a functionally significant polymorphism that is associated with moderately reduced tyrosinase catalytic activity. In this family, all of the individuals with the OA phenotype are either homozygous or heterozygous for TYR(R402Q), and heterozyous for the 1 bp deletion in MITF This suggests that the WS2-OA phenotype may result from digenic interaction between a gene for a transcription factor (MITF) and a gene that it regulates (TYR).

Albinism, Ocular↗
PubMed1997

Mouse pale ear (ep) is homologous to human Hermansky-Pudlak syndrome and contains a rare 'AT-AC' intron.

Hermansky-Pudlak syndrome (HPS) is a rare, often fatal, autosomal recessive disorder in which albinism, bleeding and lysosomal storage are associated with defects of diverse cytoplasmic organelles, including melanosomes, platelet dense granules and lysosomes. Similar multi-organellar defects occur in the Chediak-Higashi syndrome (CHS), as well as in a large number of different mouse mutants. The HPS gene is located in 10q23, and two genetically distinct mouse loci, pale ear (ep) and ruby-eye (ru), both with mutant phenotypes similar to human HPS, map close together in the homologous region of murine chromosome 19, suggesting that one of these loci might be homologous to human HPS. We recently identified the human HPS gene, which encodes a novel ubiquitously-expressed transmembrane protein of unknown function. Here, we describe characterization of the mouse Hps cDNA and genomic locus, and identification of pathologic Hps gene mutations in ep but not in ru mice, establishing mouse pale ear as an animal model for human HPS. The phenotype of homozygous ep mutant mice encompasses those of both HPS and CHS, suggesting that these disorders may be closely related. In addition, the mouse and human HPS genes both contain a rare 'AT-AC' intron, and comparison of the sequences of this intron in the mouse and human genes identified conserved sequences that suggest a possible role for pre-mRNA secondary structure in excision of this rare class of introns.

Albinism, Oculocutaneous↗
PubMed1997

Mutations in the Chediak-Higashi syndrome gene (CHS1) indicate requirement for the complete 3801 amino acid CHS protein.

Chediak-Higashi syndrome (CHS) is a rare, usually fatal, autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, progressive neurologic dysfunction and a bleeding diathesis. The hallmark of CHS is giant organelles and giant granules in many different cell types, most likely the result of defective trafficking of specific organellar and granular proteins necessary for the normal genesis, structure or function of these cytoplasmic components. The CHS1 gene has recently been identified and shown to be homologous to the beige locus of the mouse; however, there has been disagreement as to the length of the functional CHS1 mRNA and protein. Here we report homozygous CHS1 gene mutations in two of the original probands we used to map the gene to 1q42-q44. One of these, a frameshift at codon 3197, supports our assertion that the functional CHS protein is a predicted 3801 amino acid polypeptide encoded by a 13.5 kb mRNA.

Chediak-Higashi Syndrome↗
PubMed1997

Complementation of hypopigmentation in p-mutant (pink-eyed dilution) mouse melanocytes by normal human P cDNA, and defective complementation by OCA2 mutant sequences.

Mutations in the P gene of humans and the homologous p-locus of mice, respectively, result in the homologous disorders oculocutaneous albinism type 2 (OCA2) and pink-eyed dilution. Although clearly required for melanin biosynthesis, the specific function of the P gene product, a melanosomal transmembrane protein expressed in melanocytes of the skin, hair, and eyes, is not yet known. Here we describe lines of immortal melanocytes and melanoblasts from mice of the null genotype p(cp)/p(25H). These p-null melanocytes were severely hypopigmented, although they and the melanoblasts expressed mRNAs for a number of melanosomal proteins. Proliferation of the p-null melanoblasts was normal. Both diploid and immortal p-null melanocytes grew more slowly than wild-type melanocytes, however, and were unusually susceptible to the antibiotic G418; these abnormalities were corrected by culture in high concentrations of L-tyrosine. Transfection of the p-null melanocytes with full-length normal human P cDNA resulted in complementation of deficient melanin biosynthesis and hypopigmentation. In contrast, transfection with mutant human P cDNAs containing amino acid substitutions (A481T, V443I) found in patients with OCA2 resulted in minimal or partial correction, consistent with the corresponding pigmentation phenotypes in patients with these mutations. These results demonstrate the utility of this model system for distinguishing true OCA2 mutations from nonpathologic polymorphisms and for quantitating the effect of these mutations on P function.

Albinism, Oculocutaneous↗
PubMed1997

Organization and nucleotide sequence of the human Hermansky-Pudlak syndrome (HPS) gene.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding tendency, and lysosomal ceroid storage disease, associated with defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. HPS is frequently fatal and is the most common single-gene disorder in Puerto Rico. We previously characterized the human HPS cDNA and identified pathologic mutations in the gene in patients with HPS. The HPS protein is a novel apparent transmembrane polypeptide that seems to be crucial for normal organellar development. Here we describe the structural organization, nucleotide sequence, and polymorphisms of the human HPS gene. The gene consists of 20 exons spanning about 30.5 kb in chromosome segment 10q23.1-q23.3. One of the intervening sequences is a member of the novel, very rare class of so-called "AT-AC" introns, defined by highly atypical 5' and 3' splice site and branch site consensus sequences that provide novel targets for possible pathologic gene mutations. This information provides the basis for molecular analyses of patients with HPS and will greatly facilitate diagnosis and carrier detection of this severe disorder.

Albinism, Oculocutaneous↗
PubMed1997

Mutational analysis of copper binding by human tyrosinase.

Tyrosinase (EC 1.14.18.1) is a copper-containing enzyme that catalyzes several reactions in the biosynthesis of melanin pigments and is deficient in patients with type I oculocutaneous albinism (OCA1). Tyrosinase is thought to bind two copper ions, one at each of two conserved sequence motifs, termed CuA and CuB, but to date this has been directly proved only for the Neurospora and mushroom enzyme. Here, we demonstrate that mammalian tyrosinase directly binds copper, and that the CuA and CuB sites are both required for copper binding and for catalytic activity. We show that in human tyrosinase, copper binding by the CuB site is most likely coordinated by residues His363, His367, and His389, and that copper binding may be cooperative, with copper binding at one site facilitating copper binding by the other site. Furthermore, correct folding of the tyrosinase polypeptide appears to be necessary for copper binding, and a number of human OCA1 mutations disrupt copper binding and thus catalytic function of tyrosinase.

Conserved Sequence↗
PubMed1996

Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles.

Hermansky-Pudlak syndrome (HPS) is an often-fatal autosomal recessive disease in which albinism, bleeding, and lysosomal storage result from defects of diverse cytoplasmic organelles: melanosomes, platelet dense bodies, and lysosomes. HPS is the most common single-gene disorder in Puerto Rico, with an incidence of 1 in 1,800. We have identified the HPS gene by positional cloning, and found homozygous frameshifts in this gene in Puerto Rican, Swiss, Irish and Japanese HPS patients. The HPS polypeptide is a novel transmembrane protein that is likely to be a component of multiple cytoplasmic organelles and that is apparently crucial for their normal development and function. The different clinical phenotypes associated with the different HPS frameshifts we observed suggests that differentially truncated HPS polypeptides may have somewhat different consequences for subcellular function.

Albinism, Oculocutaneous↗
PubMed1996

Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome.

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by hypopigmentation, severe immunologic deficiency with neutropenia and lack of natural killer (NK) cells, a bleeding tendency and neurologic abnormalities. Most patients die in childhood. The CHS hallmark is the occurrence of giant inclusion bodies and organelles in a variety of cell types, and protein sorting defects into these organelles. Similar abnormalities occur in the beige mouse, the proposed model for human CHS. Two groups have recently reported the identification of the beige gene, however the two cDNAs were not at all similar. Here we describe the sequence of a human cDNA homologous to mouse beige, identify pathologic mutations and clarify the discrepancies of the previous reports. Analysis of the CHS polypeptide demonstrates that its modular architecture is similar to the yeast vacuolar sorting protein, VPS15.

Adult↗
PubMed1996

Genomic organization and sequence of D12S53E (Pmel 17), the human homologue of the mouse silver (si) locus.

We have determined the DNA sequence and genomic organization of D12S53E (Pmel 17), the human homologue of the mouse silver (si) locus. D12S53E encodes a melanosomal matrix protein whose expression is closely correlated with cellular melanin content and which is a frequent melanoma tumor antigen recognized by cytotoxic T lymphocytes. D12S53E is a likely candidate gene for some cases of human oculocutaneous albinism not associated with known albinism loci.

Alternative Splicing↗