PubMed Health⌕ Search

Biomedical subjects

R A Spritz

Publications and source records attributed to R A Spritz.

At least 19 recordsLinked to original sources
PubMed2001

Duplication of 15q11.2-q14, including the P gene, in a woman with generalized skin hyperpigmentation.

We describe a woman with 15q11.2-q14 duplication who had clinical manifestations of proximal 15q trisomy and hyperpigmentation. Within this region, the P gene, located at chromosome segment 15q11.2-q12, is associated with oculocutaneous albinism type II (OCA2) and with hypopigmentation in the Prader-Willi and Angelman chromosome 15q deletion syndromes. We therefore hypothesized that in this woman skin hyperpigmentation might result from a duplication of the P gene. We carried out chromosomal and interphase fluorescence in situ hybridization (I-FISH) analyses, and determined that the P gene is duplicated in this woman. Our findings demonstrate that trisomy of the P gene can be associated with skin hyperpigmentation.

Carrier Proteins↗
PubMed2001

The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation.

Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disease resulting from mutations of the tyrosinase gene (TYR). To elucidate the molecular basis of OCA1 phenotypes, we analysed the early processing and maturation of several different types of mutant tyrosinase with various degrees of structural abnormalities (i.e. two large deletion mutants, two missense mutants that completely destroy catalytic function and three missense mutants that have a temperature-sensitive phenotype). When expressed in COS7 cells, all mutant tyrosinases were sensitive to endoglycosidase H digestion, and immunostaining showed their localization in the endoplasmic reticulum (ER) and their failure to be sorted further to their target organelles. Pulse-chase experiments showed that all mutant tyrosinases were retained by calnexin in the ER and that they were degraded at similarly rapid rates, which coincided with their dissociation from calnexin. Temperature-sensitive mutant enzymes were sorted more efficiently at 31 degrees C than at 37 degrees C, and their degradation was accelerated at 37 degrees C compared with 31 degrees C. Thus in contrast to the current concept that mutant tyrosinases are transported to melanosomes but are functionally inactive there, our results suggest that mutant tyrosinases may not be transported to melanosomes in the first place. We conclude that a significant component of mutant tyrosinase malfunction in OCA1 results from their retention and degradation in the ER compartment. This quality-control process is highly sensitive to minimal changes in protein folding, and so even relatively minor mutations in peripheral sequences of the enzyme not involved with catalytic activity may result in a significant reduction of functional enzyme in melanosomes.

Albinism, Oculocutaneous↗
PubMed2001

The gene mutated in cocoa mice, carrying a defect of organelle biogenesis, is a homologue of the human Hermansky-Pudlak syndrome-3 gene.

Hermansky-Pudlak syndrome (HPS) is a group of human disorders of organelle biogenesis characterized by defective synthesis of melanosomes, lysosomes, and platelet dense granules. In the mouse, at least 15 loci are associated with mutant phenotypes similar to human HPS. We have identified the gene mutated in cocoa (coa) mice, which is associated with an HPS-like mutant phenotype and thus represents a strong candidate for human HPS. Analysis of coa-mutant mice and cultured coa-mutant mouse melanocytes indicates that the normal coa gene product is involved in early stages of melanosome biogenesis and maturation.

Alleles↗
PubMed2001

Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela.

Non-syndromic cleft lip with or without cleft palate (CL/P, MIM 119530) is among the most common of major birth defects. Homozygosity for a nonsense mutation of PVRL1, W185X, results in an autosomal recessive CL/P syndrome on Margarita Island, CLPED1 (ref. 1). Here we demonstrate highly significant association between heterozygosity for this mutation and sporadic, non-syndromic CL/P in northern Venezuela.

Cell Adhesion Molecules↗
PubMed2001

The genetics and epigenetics of orofacial clefts.

Orofacial clefts (cleft lip, cleft palate) are among the most common of all major birth defects, but very little is known about their causation. Genetic factors are thought to play a major role, and there has been considerable recent effort to map and identify genes that constitute risk factors for clefts. This review will put into perspective the frequently-conflicting results of these studies.

Cleft Lip↗
PubMed2000

The Hermansky-Pudlak syndrome (HPS) protein is part of a high molecular weight complex involved in biogenesis of early melanosomes.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder in which oculocutaneous albinism, bleeding tendency and a ceroid-lipofuscin lysosomal storage disease result from defects of multiple cytoplasmic organelles: melanosomes, platelet dense granules and lysosomes. The HPS polypeptide, a 700 amino acid protein which is unrelated to any known proteins, is likely to be involved in the biogenesis of these different organelles. Here, we show that HPS is a non-glycosylated, non-membrane protein which is a component of two distinct high molecular weight complexes. In non-melanotic cells the HPS protein is contained almost entirely in an approximately 200 kDa complex that is widely distributed throughout the cytosol. In melanotic cells the HPS protein is partitioned between this cytosolic complex and a >500 kDa complex that appears to consist of the approximately 200 kDa complex in association with membranous components. Subcellular fractionation, immunofluorescence and immunoelectron microscopy studies indicate that the membrane-associated HPS complex of melanotic cells is associated with tubulovesicular structures, small non-coated vesicles, and nascent and early-stage melanosomes. These findings suggest that the HPS complex is involved in the biogenesis of early melanosomes.

Albinism, Oculocutaneous↗
PubMed2000

Hermansky-Pudlak syndrome and pale ear: melanosome-making for the millennium.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized principally by oculocutaneous albinism, a bleeding tendency, and a ceroid-lipofuscin lysosomal storage disease. These clinical manifestations of HPS are associated with defects of multiple cytoplasmic organelles--melanosomes, platelet granules, and lysosomes--suggesting that the HPS gene product is involved in some shared feature of the biogenesis or functions of these diverse organelles. The HPS gene has been cloned, and a number of pathologic mutations of the gene have been identified. Functional studies indicate that the HPS protein is part of a high-molecular weight complex involved in the biogenesis of early melanosomes. Additional disorders with similarities to HPS have been identified in man, mouse, flies, and yeast, and it is rapidly becoming clear that understanding these disorders will shed new light on the mechanisms by which cells traffic newly synthesized proteins through the cytoplasm to assemble functional organelles.

Albinism, Oculocutaneous↗
PubMed2000

Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia.

Cleft lip, with or without cleft palate (CL/P), is one of the most common birth defects, occurring in 0.4 to 2.0 per 1,000 infants born alive. Approximately 70% of CL/P cases are non-syndromic (MIM 119530), but CL/P also occurs in many single-gene syndromes, each affecting a protein critical for orofacial development. Here we describe positional cloning of the gene responsible for an autosomal recessive CL/P-ectodermal dysplasia (ED) syndrome (CLPED1; previously ED4; ref. 2), which we identify as PVRL1, encoding nectin-1, an immunoglobulin (Ig)-related transmembrane cell-cell adhesion molecule that is part of the NAP cell adhesion system. Nectin-1 is also the principal cell surface receptor for alpha-herpesviruses (HveC; ref. 7), and the high frequency of CLPED1 on Margarita Island in the Caribbean Sea might result from resistance of heterozygotes to infection by these viruses.

Amino Acid Sequence↗
PubMed1999

Multi-organellar disorders of pigmentation: intracellular traffic jams in mammals, flies and yeast.

Several different mutant genes in humans, mice and Drosophila, most of which were identified initially on the basis of reduced pigmentation, have been associated with defects of multiple cytoplasmic organelles - melanosomes, lysosomes and granules. Recent discoveries show that several of these mutations directly affect components in the pathway of organelle-specific protein trafficking, and provide new insights into the relationships of these pathways in mammals, flies and yeast.

Animals↗
PubMed1998

Metal ligand-binding specificities of the tyrosinase-related proteins.

The production of pigment in mammalian melanocytes requires the interaction of at least 3 melanogenic enzymes, which regulate the type and amount of melanins produced. All 3 known enzymes belong to the TRP gene family and share many common structural features, including two metal binding domains thought to be important to their catalytic functions. This study used radiolabeled metal ligand binding with autoradiography as well as reconstitution protocols to analyze the binding of metal cations to these enzymes. The results demonstrate that all 3 enzymes are capable of binding divalent metal cations; copper is bound to tyrosinase but not to TRP1 or TRP2. TRP2 requires zinc as its metal ligand, and small amounts of iron bound to TRP2; TRP1 did not bind copper, zinc or iron. Clearly, the specific binding of different metals by the TRPs is responsible for their distinct catalytic functions in melanogenesis.

Amino Acid Sequence↗
PubMed1998

Piebaldism with deafness: molecular evidence for an expanded syndrome.

In a South African girl of Xhosa stock with severe piebaldism and profound congenital sensorineural deafness we identified a novel missense substitution at a highly conserved residue in the intracellular kinase domain of the KIT proto-oncogene, R796G. Though auditory anomalies have been observed in mice with dominant white spotting (W) due to KIT mutations, deafness is not typical in human piebaldism. Thus, the occurrence of sensorineural deafness in this patient extends considerably the phenotypic range of piebaldism due to KIT gene mutation in humans and tightens the clinical similarity between piebaldism and the various forms of Waardenburg syndrome.

Amino Acid Substitution↗
PubMed1998

Genetic defects in Chediak-Higashi syndrome and the beige mouse.

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive, multisystem disorder in which severe immune deficits are accompanied by abnormalities of pigmentation, blood clotting, and neurologic function. There is no specific treatment, and without bone marrow transplantation, most patients succumb to frequent bacterial infections or to a lymphoproliferative syndrome that appears to result principally from lack of natural killer cell function. Disorders similar to human CHS occur in many mammalian species, the most important being the beige mouse, long considered a likely homologue of human CHS. This supposition has recently been confirmed by the mapping, cloning, and mutation analysis of the homologous human CHS1 and mouse beige genes. Identification of the human CHS1 gene, and the availability of a ready mouse model for human CHS, will likely facilitate investigation of the disease pathophysiology and the development of novel and specific treatments for the disorder.

Animals↗
PubMed1998

Molecular genetics of the Hermansky-Pudlak and Chediak-Higashi syndromes.

Hermansky-Pudlak syndrome(HPS) and Chediak-Higashi syndrome(CHS) are similar but distinct autosomal recessive genetic diseases in which a bleeding diathesis resulting from platelet storage pool deficiency is accompanied by deficient pigmentation of the skin and hair and various systemic abnormalities associated with defective lysosomal function. The diverse multi-systemic manifestations of HPS and CHS are associated with abnormalities of a number of different cytoplasmic organelles--platelet dense granules, melanosomes, lysosomes and various cytoplasmic secretory granules. Though rare, HPS and CHS probably represent just the first of what will eventually be a novel class of genetic disorders resulting from defective biogenesis, structure or function of these organelles. The genes responsible for HPS and CHS have recently been identified and are beginning to yield insights into the molecular genetics and cellular pathophysiology of these intriguing disorders.

Journal Article↗
PubMed1998

Mutation analysis of patients with Hermansky-Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus heterogeneity.

Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally cloned the gene, and identified three pathologic mutations of the gene, in patients from Puerto Rico, Japan, and Europe. Here, we describe mutation analysis of 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication, the result of an apparent founder effect, is nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. We also describe six novel HPS mutations: a 5' splice-junction mutation of IVS5, three frameshifts, a nonsense mutation, and a one-codon in-frame deletion. These mutations define an apparent frameshift hot spot at codons 321-322. Overall, however, we detected mutations in the HPS gene in only about half of non-Puerto Rican patients, and we present evidence that suggests locus heterogeneity for HPS.

Albinism, Oculocutaneous↗