Biomedical subjects

Y Anikster

Publications and source records attributed to Y Anikster.

At least 19 recordsLinked to original sources

PubMed2006

Infusion of platelets transiently reduces nucleoside overload in MNGIE.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by thymidine phosphorylase (TP) deficiency, which leads to toxic accumulations of thymidine (dThd) and deoxyuridine (dUrd). In this work, we report that infusion of platelets from healthy donors to patients with MNGIE restored transiently circulating TP and reduced plasma dThd and dUrd levels, suggesting that treatments to achieve permanent restoration of circulating TP such as allogeneic stem cell transplantation or gene transfer might be therapeutic.

Adolescent↗

PubMed2004

The influence of space in genetic-environmental relationships when environmental heterogeneity and seed dispersal occur at similar scale.

We tested the importance of microenvironmental topographic parameters as predictors of emmer wheat genetic variation using three classes of single-locus (or at most several-loci) genetic markers (allozymes, glutenins, and qualitative traits) and two classes of markers of polygenic inheritance (phenological and morphological traits). Canonical correspondence analysis (CCA) and redundancy analysis (RDA) detected a significant effect of spatially structured environmental variation on genetic differences between plants for allozymes, glutenins, and quantitative morphological and phenological traits. However, after removing a spatial component of variation in partial CCA and partial RDA, the relationship of the remaining environmental variation with these genetic markers could be explained by chance alone, allowing us to rule out microniche topographic specialization in emmer wheat. Topographic autocorrelation exhibited a certain degree of similarity with genetic marker autocorrelation, indicating similar scales of environmental heterogeneity and seed flow. The detected population genetic structure agrees with one expected under isolation by distance as a result of limited gene flow. A negative relationship of genetic similarity with the logarithm of distance between plants was detected for both molecular markers and quantitative traits, which differed in the strength but not the pattern of association.

Alleles↗

PubMed2001

Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews.

Type III 3-methylglutaconic aciduria (MGA) (MIM 258501) is a neuro-ophthalmologic syndrome that consists of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is increased. The disorder has been reported in approximately 40 patients of Iraqi Jewish origin, allowing the mapping of the disease to chromosome 19q13.2-q13.3, by linkage analysis. To isolate the causative gene, OPA3, we sequenced four genes within the critical interval and identified, in the intronic sequence of a gene corresponding to cDNA clone FLJ22187, a point mutation that segregated with the type III MGA phenotype. The FLJ22187-cDNA clone, which we identified as the OPA3 gene, consists of two exons and encodes a peptide of 179 amino acid residues. Northern blot analysis revealed a primary transcript of approximately 5.0 kb that was ubiquitously expressed, most prominently in skeletal muscle and kidney. Within the brain, the cerebral cortex, the medulla, the cerebellum, and the frontal lobe, compared to other parts of the brain, had slightly increased expression. The intronic G-->C mutation abolished mRNA expression in fibroblasts from affected patients and was detected in 8 of 85 anonymous Israeli individuals of Iraqi Jewish origin. Milder mutations in OPA3 should be sought in patients with optic atrophy with later onset, even in the absence of additional neurological abnormalities.

Amino Acid Sequence↗

PubMed2001

Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency.

Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non-Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G-->A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G-->A mutation and for either an 1831+2T-->G or a 2621-2A-->G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G-->A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G-->C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS.

Adaptor Protein Complex 3↗

PubMed2001

The promoter of a lysosomal membrane transporter gene, CTNS, binds Sp-1, shares sequences with the promoter of an adjacent gene, CARKL, and causes cystinosis if mutated in a critical region.

Although >55 CTNS mutations occur in patients with the lysosomal storage disorder cystinosis, no regulatory mutations have been reported, because the promoter has not been defined. Using CAT reporter constructs of sequences 5' to the CTNS coding sequence, we identified the CTNS promoter as the region encompassing nucleotides -316 to +1 with respect to the transcription start site. This region contains an Sp-1 regulatory element (GGCGGCG) at positions -299 to -293, which binds authentic Sp-1, as shown by electrophoretic-mobility-shift assays. Three patients exhibited mutations in the CTNS promoter. One patient with nephropathic cystinosis carried a -295 G-->C substitution disrupting the Sp-1 motif, whereas two patients with ocular cystinosis displayed a -303 G-->T substitution in one case and a -303 T insertion in the other case. Each mutation drastically reduced CAT activity when inserted into a reporter construct. Moreover, each failed either to cause a mobility shift when exposed to nuclear extract or to compete with the normal oligonucleotide's mobility shift. The CTNS promoter region shares 41 nucleotides with the promoter region of an adjacent gene of unknown function, CARKL, whose start site is 501 bp from the CTNS start site. However, the patients' CTNS promoter mutations have no effect on CARKL promoter activity. These findings suggest that the CTNS promoter region should be examined in patients with cystinosis who have fewer than two coding-sequence mutations.

Adult↗

PubMed2001

Molecular cloning and characterization of human VPS18, VPS 11, VPS16, and VPS33.

In multicellular organisms, the delivery of proteins to lysosomes is essential. Many of the genes necessary for this process have first been identified by their requirement for vacuolar delivery in yeast. A subset of these genes, the four class C vps genes, is necessary for the delivery of endocytic and biosynthetic cargo in yeast, and also in Drosophila. Here, we describe the sequence and expression pattern of four human homologs of these genes. This initial molecular description of these four genes is an important step towards their evaluation as candidate genes that may be involved in the pathogenesis of Hermansky-Pudlak syndrome-related diseases.

Amino Acid Sequence↗

PubMed2001

Mutation analysis of the MCM gene in Israeli patients with mut(0) disease.

Three novel mutations (IVS8+3a --> g, N219Y, and E414X) were identified in 6 unrelated patients with mut(0) methylmalonic aciduria. The presence of a wild-type along with rearranged fragments in homozygotes for the IVS8+3a --> g mutation may contribute to their later age of onset (3-11 months of age). Nonetheless, delayed onset was not associated with better neurological outcome and prolonged survival. The large number of undiagnosed dead sibs in most families suggests that the disease is largely underdiagnosed in this region.

Amino Acid Metabolism, Inborn Errors↗

PubMed2001

CTNS mutations in African American patients with cystinosis.

Cystinosis, an autosomal recessive lysosomal storage disorder, is rarely diagnosed in African Americans. The disease results from mutations in the gene CTNS; at least 55 such mutations have been reported. By far the most common is a 57,257-bp deletion of Northern European origin encompassing most of the CTNS gene. We performed mutation analysis on DNA from four African American patients with cystinosis. In one individual with classical, nephropathic cystinosis, we identified a new molecular defect, i.e., a homozygous GT-->CC substitution at the +5 position of IVS 5 of CTNS (IVS 5+5 GT-->CC). The out-of-frame splicing of exon 5 creates a null allele consistent with the patient's severe phenotype. Two patients were heterozygous and one homozygous for the common 57-kb deletion allele, reflecting the admixture of African and Northern European gene pools in North America. The two African Americans heterozygous for the 57-kb deletion were also hemizygous for a 928G-->A change, associated with ocular or nonnephropathic cystinosis. These two individuals are the only known African Americans with ocular cystinosis. We conclude that the diagnosis of cystinosis should be entertained in African Americans with symptoms of the disease, and that mutation analysis for the 57-kb deletion should be considered in this group of patients.

Adolescent↗

PubMed2001

A new genetic isolate of gray platelet syndrome (GPS): clinical, cellular, and hematologic characteristics.

Gray platelet syndrome (GPS) is a disorder characterized by thrombocytopenia and large platelets that lack alpha granules and their contents. We describe two siblings with GPS who are members of a Moslem Bedouin genetic isolate. The children, an 8-year-old girl and a 5-year-old boy, had characteristic pale blue platelets lacking alpha granules on electron microscopy. Platelet aggregation studies were normal. The girl underwent a bone marrow aspiration and biopsy which showed mild myelofibrosis and extensive emperipolesis, i.e., the passage of other hematopoietic cells through megakaryocytes. Both children lacked high-molecular-weight multimers of von Willebrand factor (vWF) and had reduced activity and antigens of vWf. Platelet activation was approximately normal when ADP was employed as agonist, but significantly impaired using the thrombin receptor-activating peptide (TRAP). These findings are explained in light of the mechanism of action of each agonist. In addition, we propose that the emperipolesis was caused by increased P-selectin in megakaryocytes, and resulted in release of fibroblastic growth factors, explaining the myelofibrosis. The detailed description of these cases provides a basis for future differentiation of the various types of GPS, and for our current attempts to isolate the gene causing GPS in this genetic isolate.

Adenosine Diphosphate↗

PubMed2001

Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies. Lysosomal ceroid lipofuscinosis, pulmonary fibrosis and granulomatous colitis are occasional manifestations of the disease. HPS occurs with a frequency of one in 1800 in north-west Puerto Rico due to a founder effect. Several non-Puerto Rican patients also have mutations in HPS1, which produces a protein of unknown function. Another gene, ADTB3A, causes HPS in the pearl mouse and in two brothers with HPS-2 (refs. 11,12). ADTB3A encodes a coat protein involved in vesicle formation, implicating HPS as a disorder of membrane trafficking. We sought to identify other HPS-causing genes. Using homozygosity mapping on pooled DNA of 6 families from central Puerto Rico, we localized a new HPS susceptibility gene to a 1.6-cM interval on chromosome 3q24. The gene, HPS3, has 17 exons, and a putative 113.7-kD product expected to reveal how new vesicles form in specialized cells. The homozygous, disease-causing mutation is a large deletion and represents the second example of a founder mutation causing HPS on the small island of Puerto Rico. We also present an allele-specific assay for diagnosing individuals heterozygous or homozygous for this mutation.

Alleles↗

PubMed2001

Pulmonary dysfunction in adults with nephropathic cystinosis.

OBJECTIVE: To characterize the pulmonary dysfunction in patients with nephropathic cystinosis after renal transplantation. DESIGN: Cross-sectional analysis of consecutive adult patients. PATIENTS: Twelve adult, nephropathic cystinosis patients and 3 adult, ocular, nonnephropathic cystinosis patients admitted to the National Institutes of Health Clinical Center. RESULTS: The 12 nephropathic cystinosis patients (age range, 21 to 40 years) showed an extraparenchymal pattern of restrictive lung disease, with inspiratory and expiratory dysfunction. Specifically, the mean FVC was 58% of predicted, the mean FEV(1) was 57% of predicted, and the mean total lung capacity was 66% of predicted, while the mean residual volume was normal. Furthermore, the mean maximal inspiratory pressure for the eight patients tested was 40% of predicted, and the mean maximal expiratory pressure was 26% of predicted. Two patients died of respiratory insufficiency. All the patients had lived at least 17 years, while lacking compliant cystine-depleting therapy with oral cysteamine. Seven patients had a conical chest, restricting excursion, and 10 of the 12 patients had evidence of the myopathy that typifies late cystinosis. In fact, the severity of pulmonary disease correlated directly with the severity of myopathy in our group of 12 patients. In contrast, the lung parenchyma was essentially normal, as gauged by chest radiographs and CT scans of the lung. The three patients with nonnephropathic cystinosis displayed entirely normal pulmonary function. CONCLUSION: The distal myopathy characteristic of nephropathic cystinosis results in an extraparenchymal pattern of restrictive lung disease in adults who have not received long-term cystine depletion. Whether or not oral cysteamine therapy can prevent this complication remains to be determined.

Adult↗

PubMed2001

Hermansky-Pudlak syndrome and Chediak-Higashi syndrome: disorders of vesicle formation and trafficking.

The rare autosomal recessive metabolic disorders Hermanky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS)share the clinical findings of oculocutaneous albinism and a platelet storage pool deficiency. In addition, HPS exhibits ceroid lipofuscinosis and CHS is characterized by infections and an accelerated phase. The two disorders result from defects in vesicles of lysosomal lineage. Of the two known HPS-causing genes, HPS1 has no recognizable function, while ADTB3A codes for a subunit of an adaptor complex responsible for new vesicle formation from the trans-Golgi network. Other HPS-causing genes are likely to exist. The only known CHS-causing gene, LYST, codes for a large protein of unknown function. In general, HPS appears to be a disorder of vesicle formation and CHS a defect in vesicle trafficking. These diseases and their variants mirror a group of mouse hypopigmentation mutants. The gene productsinvolved will reveal how the melanosome, platelet dense body, and lysosome are formed and trafficked within cells.

Animals↗

PubMed2000

Characterization of a partial pseudogene homologous to the Hermansky-Pudlak syndrome gene HPS-1; relevance for mutation detection.

The HPS-1 gene is the first gene found to be responsible for the autosomal recessive disorder Hermansky-Pudlak syndrome (HPS). HPS is characterized by oculocutaneous albinism, a platelet storage pool deficiency, and ceroid lipofuscinosis. The HPS-1 gene has been mapped to chromosome 10q23.1-23.3 and encodes a 79-kDa protein of unknown function with no homology to any known protein. A sequence database search has revealed that a portion of clone HS 1119A7 shows high sequence similarity to HPS-1 cDNA. By performing sequence alignments and PCR amplification of cDNA from several human tissues, we have shown that part of this clone consists of an unprocessed partial HPS-1 pseudogene located on chromosome 22q12.2-12.3. The pseudogene contains several intact HPS-1 exons and shows 95% sequence homology to the HPS-1 cDNA. Exon 6 of the pseudogene has 100% sequence homology to exon 6 of HPS-1 itself. In the pseudogene, this exon is surrounded by portions of both its normal flanking introns. These data provide the first characterization of an HPS-1 pseudogene, called HPS1-psi1. During amplification of exon 6 of the HPS-1 gDNA for mutation identification, the pseudogene might also be amplified, leading to a false positive for mutation. In addition, amplification of specific parts of the HPS-1 cDNA (e.g., exons 2-5) for mutation detection might lead to false positives for mutations, if the cDNA is contaminated with gDNA. This calls for caution when employing these screening approaches.

Albinism, Oculocutaneous↗

PubMed2000

Hermansky-Pudlak syndrome and related disorders of organelle formation.

Hermansky-Pudlak syndrome (HPS) consists of a group of genetically heterogeneous disorders which share the clinical findings of oculocutaneous albinism, a platelet storage pool deficiency, and some degree of ceroid lipofuscinosis. Related diseases share some of these findings and may exhibit other symptoms and signs but the underlying defect in the entire group of disorders involves defective intracellular vesicle formation, transport or fusion. Two HPS-causing genes, HPS1 and ADTB3A, have been isolated but the function of only the latter has been determined. ADTB3A codes for the beta 3A subunit of adaptor complex-3, responsible for vesicle formation from the trans-Golgi network (TGN). The many HPS patients who do not have HPS1 or ADTB3A mutations have their disease because of mutations in other genes. Candidates for these HPS-causing genes include those responsible for mouse models of HPS or for the 'granule' group of eye color genes in Drosophila. Each gene responsible for a subset of HPS or a related disorder codes for a protein which almost certainly plays a pivotal role in vesicular trafficking, inextricably linking clinical and cell biological interests in this group of diseases.

Animals↗

PubMed2000

The genomic region encompassing the nephropathic cystinosis gene (CTNS): complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion.

Nephropathic cystinosis is an autosomal recessive disorder caused by the defective transport of cystine out of lysosomes. Recently, the causative gene (CTNS) was identified and presumed to encode an integral membrane protein called cystinosin. Many of the disease-associated mutations in CTNS are deletions, including one >55 kb in size that represents the most common cystinosis allele encountered to date. In an effort to determine the precise genomic organization of CTNS and to gain sequence-based insight about the DNA within and flanking cystinosis-associated deletions, we mapped and sequenced the region of human chromosome 17p13 encompassing CTNS. Specifically, a bacterial artificial chromosome (BAC)-based physical map spanning CTNS was constructed by sequence-tagged site (STS)-content mapping. The resulting BAC contig provided the relative order of 43 STSs. Two overlapping BACs, which together contain all of the CTNS exons as well as extensive amounts of flanking DNA, were selected and subjected to shotgun sequencing. A total of 200,237 bp of contiguous, high-accuracy sequence was generated. Analysis of the resulting data revealed a number of interesting features about this genomic region, including the long-range organization of CTNS, insight about the breakpoints and intervening DNA associated with the common cystinosis-causing deletion, and structural information about five genes neighboring CTNS (human ortholog of rat vanilloid receptor subtype 1 gene, CARKL, TIP-1, P2X5, and HUMINAE). In particular, sequence analysis detected the presence of a novel gene (CARKL) residing within the most common cystinosis-causing deletion. This gene encodes a previously unknown protein that is predicted to function as a carbohydrate kinase. Interestingly, both CTNS and CARKL are absent in nearly half of all cystinosis patients (i.e., those homozygous for the common deletion). [The sequence data described in this paper have been submitted to the GenBank data library under accession nos. AF168787 and AF163573.]

Amino Acid Transport Systems, Neutral↗

PubMed2000

Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations.

Ocular nonnephropathic cystinosis, a variant of the classic nephropathic type of cystinosis, is an autosomal recessive lysosomal storage disorder characterized by photophobia due to corneal cystine crystals but absence of renal disease. We determined the molecular basis for ocular cystinosis in four individuals. All had mutations in the cystinosis gene CTNS, indicating that ocular cystinosis is allelic with classic nephropathic cystinosis. The ocular cystinosis patients each had one severe mutation and one mild mutation, the latter consisting of either a 928 G-->A (G197R) mutation or an IVS10-3 C-->G splicing mutation resulting in the insertion of 182 bp of IVS10 into the CTNS mRNA. The mild mutations appear to allow for residual CTNS mRNA production, significant amounts of lysosomal cystine transport, and lower levels of cellular cystine compared with those in nephropathic cystinosis. The lack of kidney involvement in ocular cystinosis may be explained by two different mechanisms. On the one hand (e.g. the G197R mutation), significant residual cystinosin activity may be present in every tissue. On the other hand (e.g. the IVS 10-3 C-->G mutation), substantial cystinosin activity may exist in the kidney because of that tissue's specific expression of factors that promote splicing of a normal CTNS transcript. Each of these mechanisms could result in minimally reduced lysosomal cystine transport in the kidneys.

Amino Acid Transport Systems, Neutral↗

PubMed1999

CTNS mutations in patients with cystinosis.

Cystinosis is an autosomal recessive lysosomal storage disease caused by mutations in the gene CTNS. The CTNS gene product, cystinosin, has 367 amino acids and seven transmembrane domains and is thought to transport cystine out of lysosomes. The most common form of cystinosis, the nephropathic or infantile type, is characterized by renal failure at 10 years of age and other systemic complications. To date, 32 different CTNS mutations have been described in nephropathic cystinosis patients. Intermediate cystinosis, with later onset of renal disease, has been associated with three different CTNS mutations. Benign or nonnephropathic cystinosis, with symptoms related only to corneal crystals and photophobia, has been associated with two other CTNS mutations. In general, only certain splicing or missense mutations are associated with milder cystinosis phenotypes. Hum Mutat 14:454-458, 1999. Published 1999 Wiley-Liss, Inc.

Amino Acid Transport Systems, Neutral↗

PubMed1999

Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene (CTNS).

The most common mutation in the cystinosis gene, CTNS, is a 65-kb deletion thought to have originated in Germany. Although homozygotes for this deletion are detectable by the absence of the D17S829 polymorphic marker, no method exists to identify heterozygotes. We identified the 65-kb deletion breakpoints and used flanking PCR primers to amplify a 423-bp fragment present only in the deletion alleles. Using this method, we determined that 121 of 216 (56%) cystinosis alleles examined bore the 65-kb deletion. We found no non-Europeans with the deletion, and the deletion size and breakpoints appeared identical in all patients studied, supporting the concept of a founder effect. The addition of D17S829 primers (266 bp apart) to the PCR created a multiplex PCR system useful for diagnosing cystinosis patients homozygous and heterozygous for the 65-kb deletion.

Alleles↗