Transferrin protein variant mimicking carbohydrate-deficient glycoprotein syndrome in trisomy 7 mosaicism.
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Child, Preschool↗
Biomedical subjects
H Mandel
Publications and source records attributed to H Mandel.
Characteristic urine organic acid profile in peroxisomal biogenesis disorders.
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Adrenoleukodystrophy↗
Molecular basis of variant pseudo-hurler polydystrophy (mucolipidosis IIIC)
Mucolipidosis IIIC, or variant pseudo-Hurler polydystrophy, is an autosomal recessive disease of lysosomal hydrolase trafficking. Unlike the related diseases, mucolipidosis II and IIIA, the enzyme affected in mucolipidosis IIIC (N-Acetylglucosamine-1-phosphotransferase [GlcNAc-phosphotransferase]) retains full transferase activity on synthetic substrates but lacks activity on lysosomal hydrolases. Bovine GlcNAc-phosphotransferase has recently been isolated as a multisubunit enzyme with the subunit structure alpha(2)beta(2)gamma(2). We cloned the cDNA for the human gamma-subunit and localized its gene to chromosome 16p. We also showed, in a large multiplex Druze family that exhibits this disorder, that MLIIIC also maps to this chromosomal region. Sequence analysis of the gamma-subunit cDNA in patients from 3 families identified a frameshift mutation, in codon 167 of the gamma subunit, that segregated with the disease, indicating MLIIIC results from mutations in the phosphotransferase gamma-subunit gene. This is to our knowledge the first description of the molecular basis for a human mucolipidosis and suggests that the gamma subunit functions in lysosomal hydrolase recognition.
Amino Acid Sequence↗
Prenatal diagnosis and carrier detection for molybdenum cofactor deficiency type A in northern Israel using polymorphic DNA markers.
Molybdenum cofactor deficiency (MoCoD) is an autosomal recessive, fatal neurological disorder, characterized by the combined deficiency of sulphite oxidase, xanthine dehydrogenase and aldehyde oxidase. We have recently reported an excessive occurrence of this fatal disorder among segments of the Arab population in Northern Israel suggesting that the true incidence of MoCoD is probably underestimated in this highly inbred population. This lethal disease can be diagnosed prenatally by assay of sulphite oxidase activity in chorionic villus samples in pregnancies of couples who have had previously affected children (obligatory carriers). However, to date, there is no biochemical assay for carrier detection among the population at risk. Recently we demonstrated the linkage of a MoCoD gene to an 8-cM region on chromosome 6p21.3 in two consanguineous Israeli-Arab unrelated kindreds. The description of the MOCS1 gene that maps to the same region and which carries multiple mutations in MoCoD type A followed this finding. We describe here one additional kindred of Arab-Israeli origin, which is also linked to the MOCS1 locus, and demonstrate the feasibility of prenatal diagnosis and carrier detection using microsatellite markers in selected families when mutations are unknown. A complete correlation between the biochemical and DNA assays was found in a total of six samples (five chorionic villus and one amniocyte culture sample) obtained from the three MoCoD families.
Chorionic Villi↗
Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews.
We studied 13 patients with lipoamide dehydrogenase (LAD) deficiency, originating from seven Ashkenazi Jewish families. Their disease was characterized by recurrent attacks of vomiting, abdominal pain, and encephalopathy accompanied by elevated liver transaminases, prolonged prothrombin time, and occasionally associated with lactic and ketoacidemia or with myoglobinuria. Two patients who presented neonatally suffered from residual neurological damage with attention deficit hyperactive disorder, mild ataxia, motor incoordination, muscle hypotonia, and weakness. Nine patients who presented in early childhood or later suffered from exertional fatigue between decompensation episodes but were otherwise asymptomatic. Two patients died because of intractable metabolic acidosis and multi-organ failure. In all patients LAD activity was reduced to 8 to 21% of the control in muscle or lymphocytes. In four patients LAD protein in muscle was reduced to 20 to 60% of the control. Direct sequencing of the cDNA of the LAD gene showed that 12 of the 14 mutated alleles carried the G229C mutation and two carried an insertion mutation 105insA (Y35X). The patients who presented neonatally and had more severe sequelae were compound heterozygotes for the two mutations; patients who presented in early childhood or later were homozygous for the G229C mutation. Using an allele-specific oligonucleotide hybridization technique, nine heterozygotes for the G229C mutation were identified among 845 anonymous individuals of Ashkenazi Jewish origin disclosing a carrier rate of 1:94. Because of the significant morbidity associated with the disease, screening for the G229C mutation among Ashkenazi Jewish couples should be considered.
Adult↗
Prenatal diagnosis of non-ketotic hyperglycinaemia: enzymatic diagnosis in 28 families and DNA diagnosis detecting prevalent Finnish and Israeli-Arab mutations.
Prenatal diagnosis for non-ketotic hyperglycinaemia (NKH) was performed by enzymatic analysis of chorionic villus samples in 28 families and by DNA analysis in two families. In 26 families, enzymatic analysis of the glycine cleavage multi-enzyme system (GCS) yielded an unambiguous diagnosis; inconclusive results in two families were due to borderline GCS activity. We analysed a second chorionic sample in these two families. In one case, GCS activity was normal in the second specimen, and the baby did not have NKH. In the other case, we again found extremely low GCS activity in the second specimen, but a healthy baby was born. The cause of this false-positive result is unknown. Molecular analysis of NKH has identified two prevalent mutations to date; the S564I mutation in a gene encoding the P-protein, a component of the GCS, in a Finnish population, and the H42R mutation in a gene encoding the T-protein in the Israeli-Arab population. These prevalent mutations allow us to obtain unambiguous prenatal diagnoses in both Finnish and Israeli-Arab families. GCS activity in samples from a Finnish family demonstrated a good agreement with DNA analysis, but the fetus of the Israeli-Arab family had an upper limit activity of the affected range, suggesting an advantages for DNA analysis.
Amino Acid Oxidoreductases↗
Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness.
Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers syndrome, is an early onset, autosomal recessive disorder defined by the occurrence of megaloblastic anaemia, diabetes mellitus and sensorineural deafness, responding in varying degrees to thiamine treatment (MIM 249270). We have previously narrowed the TRMA locus from a 16-cM to a 4-cM interval on chromosomal region 1q23.3 (refs 3,4) and this region has been further refined to a 1.4-cM interval. Previous studies have suggested that deficiency in a high-affinity thiamine transporter may cause this disorder. Here we identify the TRMA gene by positional cloning. We assembled a P1-derived artificial chromosome (PAC) contig spanning the TRMA candidate region. This clarified the order of genetic markers across the TRMA locus, provided 9 new polymorphic markers and narrowed the locus to an approximately 400-kb region. Mutations in a new gene, SLC19A2, encoding a putative transmembrane protein homologous to the reduced folate carrier proteins, were found in all affected individuals in six TRMA families, suggesting that a defective thiamine transporter protein (THTR-1) may underlie the TRMA syndrome.
Amino Acid Sequence↗
The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor.
Growth and function of the thyroid and adrenal glands are maintained and controlled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), respectively. The action of these trophic hormones requires the presence of functional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occurred alone or together in eight family members belonging to four nuclear families. The high serum TSH and ACTH levels in the presence of normal or hypoplastic thyroid glands and low glucocorticoid, but not mineralocorticoid concentrations, are characteristic of resistance to TSH and ACTH. Linkage analysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation was identified in exon 10 of the TSHR that replaces the normal cytosine in nucleotide 2024 with a thymidine. As a result the normal arginine in codon 609 (CGA) is replaced with a stop codon (TGA). This mutation produces a truncated TSHR lacking the third intracellular and extracellular loops, the sixth and seventh transmembrane segments, and the intracytoplasmic tail. The presence of hypothyroidism did not affect the timing, severity, and manner of clinical manifestation of hypoadrenocortisolism.
Adolescent↗
Plasmalogen phospholipids are involved in HDL-mediated cholesterol efflux: insights from investigations with plasmalogen-deficient cells.
Plasmalogens are ether-glycerophospholipids that exist in all mammalian cells, but their physiological function remains thus far an enigma. It has been previously suggested that the association of high-density lipoprotein (HDL) with cellular phospholipid is a pre-requisite for the process of HDL-mediated cholesterol efflux (HDL-MCE). To investigate our hypothesis that plasmalogens might play a role in HDL-MCE, we used a model composed of plasmalogen-deficient cells including RAW mutant macrophages and fibroblasts from patients with rhizomelic chondrodysplasia punctata type II. In mutant macrophages, HDL-MCE was reduced by 57% compared to control macrophages, after 16 hours. A similar phenomenon was observed in plasmalogen-deficient patients fibroblasts. Incubation of plasmalogen-deficient fibroblasts with 1-0-hexadecyl-sn-glycerol, which restored plasmalogen levels to that of control cells, resulted in a 35% increase in HDL-MCE, compared to a 10% increment in controls. The novel finding that HDL-MCE is reduced in plasmalogen-deficient cells and increases following plasmalogen restoration leads us to suggest that plasmalogen has an important function in the mediation of cellular cholesterol efflux.
Animals↗
Molecular basis of hepatic carnitine palmitoyltransferase I deficiency.
Mitochondrial fatty acid beta-oxidation is important for energy production, which is stressed by the different defects found in this pathway. Most of the enzyme deficiencies causing these defects are well characterized at both the protein and genomic levels. One exception is carnitine palmitoyltransferase I (CPT I) deficiency, of which until now no mutations have been reported although the defect is enzymatically well characterized. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Here we report the first delineation of the molecular basis of hepatic CPT I deficiency in a new case. cDNA analysis revealed that this patient was homozygous for a missense mutation (D454G). The effect of the identified mutation was investigated by heterologous expression in yeast. The expressed mutant CPT IA displayed only 2% of the activity of the expressed wild-type CPT IA, indicating that the D454G mutation is the disease-causing mutation. Furthermore, in patient's fibroblasts the CPT IA protein was markedly reduced on immunoblot, suggesting that the mutation renders the protein unstable.
Amino Acid Sequence↗
A missense mutation (His42Arg) in the T-protein gene from a large Israeli-Arab kindred with nonketotic hyperglycinemia.
Nonketotic hyperglycinemia (NKH) is caused by a mutation in the genes encoding the components of the glycine cleavage multi-enzyme system. More than 80% of the patients have defects in the gene encoding P-protein, whereas the rest of the patients have defects in the gene encoding T-protein. We have found a large Israeli-Arab kindred with NKH. At least 14 children were affected, and all the patients had seizures and respiratory failure within 2 days after birth. Enzymatic analysis revealed that T-protein activity was deficient in the liver specimen from one propositus. We screened this family for a mutation in the protein-coding region and exon/intron boundaries of T-protein gene by direct sequencing analysis. A missense mutation was found in exon 2; this resulted in an amino acid substitution from histidine to arginine at position 42 (H42R). Histidine 42 is conserved in human, bovine, chicken, pea, and Escherichia coli, suggesting that it has an important role in catalytic functions. Genotype analyses of 26 family members confirmed that the homozygous H42R mutation was completely associated with the onset of NKH. The availability of DNA testing facilitates the prenatal diagnosis of NKH and the identification of carriers, which is necessary for genetic counseling in the affected families.
Amino Acid Metabolism, Inborn Errors↗
Refined mapping of the gene for thiamine-responsive megaloblastic anemia syndrome and evidence for genetic homogeneity.
Thiamine-responsive megaloblastic anemia (TRMA, also known as Rogers syndrome, OMIM 249270) is a rare autosomal recessive disorder characterized by a triad of megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Patients respond, to varying degrees, to treatment with megadoses of thiamine. We have recently shown genetic linkage of the TRMA gene to a 16-centimorgan (cM) region on 1q23.2-1q23.3 based on the analysis of four large, inbred families of Alaskan, Italian, and Israeli-Arab origin. Here we narrow the TRMA interval down to 4 cM based on genetic recombination, homozygosity mapping, and linkage disequilibrium (highest LOD score of 12.5 at D1S2799, at a recombination fraction of 0). We provide further evidence that the TRMA gene is located in this region and confirm the homogeneity of the disease. In this analysis, we genotyped seven additional families of diverse ethnic origin (Pakistani, Indian, Italian, Brazilian, and Japanese), and analyzed additional markers in two previously reported families showing evidence of linkage disequilibrium in a large area of their haplotypes. The multi-system manifestations of TRMA suggest that thiamine has a pivotal role in a multiplicity of physiological processes. Mapping the TRMA gene and understanding the molecular basis of the disease might, thus, shed light on the role of thiamine in common disorders such as deafness, anemia, and diabetes.
Anemia, Megaloblastic↗
Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency.
All molybdoenzymes other than nitrogenase require molybdopterin as a metal-binding cofactor. Several genes necessary for the synthesis of the molybdenum cofactor (MoCo) have been characterized in bacteria and plants. The proteins encoded by the Escherichia coli genes moaA and moaC catalyse the first steps in MoCo synthesis. The human homologues of these genes are therefore candidate genes for molybdenum cofactor deficiency, a rare and fatal disease. Using oligonucleotides complementary to a conserved region in the moaA gene, we have isolated a human cDNA derived from liver mRNA. This transcript contains an open reading frame (ORF) encoding the human moaA homologue and a second ORF encoding a human moaC homologue. Mutations can be found in the majority of MoCo-deficient patients that confirm the functional role of both ORFs in the corresponding gene MOCS1 (for 'molybdenum cofactor synthesis-step 1'). Northern-blot analysis detected only full-length transcripts containing both consecutive ORFs in various human tissues. The mRNA structure suggests a translation reinitiation mechanism for the second ORF. These data indicate the existence of a eukaryotic mRNA, which as a single and uniform transcript guides the synthesis of two different enzymatic polypeptides with disease-causing potential.
Amino Acid Sequence↗
The gene for glycogen-storage disease type 1b maps to chromosome 11q23.
Glycogen-storage disease type 1 (GSD-1), also known as "von Gierke disease," is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase) activity. There are four distinct subgroups of this autosomal recessive disorder: 1a, 1b, 1c, and 1d. All share the same clinical manifestations, which are caused by abnormalities in the metabolism of glucose-6-phosphate (G6P). However, only GSD-1b patients suffer infectious complications, which are due to both the heritable neutropenia and the functional deficiencies of neutrophils and monocytes. Whereas G6Pase deficiency in GSD-1a patients arises from mutations in the G6Pase gene, this gene is normal in GSD-1b patients, indicating a separate locus for the disorder in the 1b subgroup. We now report the linkage of the GSD-1b locus to genetic markers spanning a 3-cM region on chromosome 11q23. Eventual molecular characterization of this disease will provide new insights into the genetic bases of G6P metabolism and neutrophil-monocyte dysfunction.
Chromosome Deletion↗
Localization of a gene for molybdenum cofactor deficiency, on the short arm of chromosome 6, by homozygosity mapping.
Molybdenum cofactor deficiency (MoCoD) is a fatal disorder manifesting, shortly after birth, with profound neurological abnormalities, mental retardation, and severe seizures unresponsive to any therapy. The disease is a monogenic, autosomal recessive disorder, and the existence of at least two complementation groups suggests genetic heterogeneity. In humans, MoCoD leads to the combined deficient activities of sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. By using homozygosity mapping and two consanguineous affected kindreds of Israeli-Arab origin, including five patients, we demonstrated linkage of a MoCoD gene to an 8-cM region on chromosome 6p21.3, between markers D6S1641 and D6S1672. Linkage analysis generated the highest combined LOD-score value, 3.6, at a recombination fraction of 0, with marker D6S1575. These results now can be used to perform prenatal diagnosis with microsatellite markers. They also provide the only tool for carrier detection of this fatal disorder.
Aldehyde Oxidase↗
Role of macrophage glycosaminoglycans in the cellular catabolism of oxidized LDL by macrophages.
Macrophage binding sites for oxidized LDL (Ox-LDL) include class A scavenger receptors (SR-As), the CD-36 molecule, and an additional but hitherto unidentified binding site. Because cell-surface glycosaminoglycans (GAGs) were previously shown to be involved in the cellular uptake of native LDL and lipoprotein(a), several strategies to assess the participation of heparan sulfate (HS) and chondroitin sulfate (CS) in macrophage catabolism of Ox-LDL were used. First, incubation of J-774 A.1 macrophage-like cells with either heparinase or chondroitinase, or with both enzymes together, reduced the binding, uptake, and degradation of 125I-Ox-LDL by 20% to 45%, in comparison with control nontreated cells, while catabolism of 125I-labeled acetylated LDL (Ac-LDL) and native LDL were unaffected. Second, the proteoglycan (PG) cellular content was increased by cell enrichment with exogenous GAGs or by using human monocyte-derived macrophages from two patients with Sanfilippo mucopolysaccharidosis, which are characterized by cellular HS accumulation. In these macrophages, cellular uptake of 125I-Ox-LDL increased, while catabolism of 125I-Ac-LDL and native LDL were unaffected. Experiments using conditioned media from control, heparinase-digested, or chondroitinase-digested macrophages indicated that neither secreted GAGs nor released digestion products played any role in Ox-LDL catabolism. To evaluate potential interactions between cell-surface GAGs and known receptors for Ox-LDL, we used excess unlabeled Ac-LDL to block SR-As or anti-CD-36 antibodies to block CD-36, and then examined the catabolism of 125I-Ox-LDL by GAG-enriched or -depleted macrophages. Both excess unlabeled Ac-LDL and anti-CD-36 antibodies reduced 125I-Ox-LDL catabolism, but only excess unlabeled Ac-LDL completely abolished the increase in 125I-Ox-LDL catabolism on GAG enrichment of the cells, indicating a cooperation between exogenous GAGs and cell-surface SR-As in the catabolism of OX-LDL. Moreover, the addition of GAGases to macrophages that were preincubated with anti-CD-36 antibodies and excess Ac-LDL further reduced macrophage degradation of Ox-LDL in comparison with cells that were pretreated only with anti-CD-36 antibodies and Ac-LDL, indicating a more complex role for endogenous GAGs. Overall, these studies demonstrate a substantial contribution of macrophage-associated GAGs in the catabolism of Ox-LDL, which is mediated in part by a cooperation between GAGs and cell-surface SR-As.
Acetylation↗
Glycogen storage disease type 1a in Israel: biochemical, clinical, and mutational studies.
Glycogen storage disease type 1a (von Gierke disease, GSD 1a) is caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) activity which catalyzes the final common step of glycogenolysis and gluconeogenesis. The recent cloning of the G6Pase cDNA and characterization of the human G6Pase gene enabled the characterization of the mutations causing GSD 1a. This, in turn, allows the introduction of a noninvasive DNA-based diagnosis that provides reliable carrier testing and prenatal diagnosis. In this study, we report the biochemical and clinical characteristics as well as mutational analyses of 12 Israeli GSD 1a patients of different families, who represent most GSD 1a patients in Israel. The mutations, G6Pase activity, and glycogen content of 7 of these patients were reported previously. The biochemical data and clinical findings of all patients were similar and compatible with those described in other reports. All 9 Jewish patients, as well as one Muslim Arab patient, presented the R83C mutation. Two Muslim Arab patients had the V166G mutation which was not found in other patients' populations. The V166G mutation, which was introduced into the G6Pase cDNA by site-directed mutagenesis following transient expression in COS-1 cells, was shown to cause complete inactivation of the G6Pase. The characterization of all GSD 1a mutations in the Israeli population lends itself to carrier testing in these families as well as to prenatal diagnosis, which was carried out in 2 families. Since all Ashkenzai Jewish patients harbor the same mutation, our study suggests that DNA-based diagnosis may be used as an initial diagnostic step in Ashkenazi Jews suspected of having GSD 1a, thereby avoiding liver biopsy.
Arabs↗
Activated protein C resistance can be associated with recurrent fetal loss.
As thrombosis of placental vessels may result in recurrent fetal loss, we analysed 39 consecutive women with recurrent fetal loss of unknown cause for activated protein C resistance. Factor V Leiden (FVL) mutation (19 cases) or APC resistance without FVL (nine cases) were found among these 39 women. Evaluation of 128 pregnancies in 19 patients with factor V Leiden mutation and 56 gestations in nine women with acquired APC resistance, revealed over 50% first-trimester abortions and 17% late abortions. Intra-uterine fetal death occurred in nine out of 19 FVL patients (47%). Only 34 of 184 gestations (18%) in hereditary or acquired APC-resistance women resulted in a live birth, with 11 of the 34 (32%) being premature deliveries. These data suggest that, in some patients with recurrent fetal loss, hereditary and acquired APC resistance are potential causes of vascular placental insufficiency.
Abortion, Habitual↗