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G Bach

Publications and source records attributed to G Bach.

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

A nonsense mutation (R242X) in the branched-chain alpha-keto acid dehydrogenase E1alpha subunit gene (BCKDHA) as a cause of maple syrup urine disease. Mutations in brief no. 160. Online.

Mutation analysis of DNA from cultured amniocytes with absent branched-chain alpha-ketoacid dehydrogenase activity revealed a C to T transition producing a nonsense mutation (R242X) in exon 7 of the gene encoding the E1a subunit of this multienzme complex (BCKDHA). This pregnancy occured in a large consanguinous pedigree with mutiple individuals with maple syrup urine disease (MSUD). PCR amplification of the region surrounding exon 7 allowed the identification of this mutation as well as two other previously identified mutations which cause MSUD.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1997

Mucolipidosis type IV: abnormal transport of lipids to lysosomes.

Mucolipidosis type IV (MLIV) is a lysosomal storage disorder in which various phospholipids and gangliosides accumulate. The cause of this storage has not yet been identified. Loading experiments in cultured fibroblasts with radioactive phosphatidylcholine ([14C]PC) labelled either in the acyl groups or in the choline residue, indicated increased retention of this lipid in the lysosomes of these patients. Chase experiments in intact fibroblasts, on the other hand, indicated normal degradation and discharge of the radioactive PC in MLIV lysosomes. This was further supported by measurements of the degradation of [14C]PC by isolated lysosomes which indicated normal breakdown of PC in MLIV. Cultured fibroblasts from Hunter (MPSII) patients, which contain enlarged and numerous lysosomes, did not store [14C]PC when compared to normal controls, indicating that the storage of this lipid in MLIV is not a secondary phenomenon caused by the presence of enlarged and numerous lysosomes in these cells. Incubation of [14C]PC at 18 degrees C limits the endocytosis process only up to early endosomes. This temperature did not yield increased retention of [14C]PC in MLIV, indicating that accumulation occurs only after the PC reached late endosomes or the lysosomes. The data indicate that PC as well as other phospholipids and gangliosides accumulate in MLIV apparently owing to a defect in the endocytosis process of membranous components. This defect apparently leads to excessive transportation of these macromolecules into lysosomes rather than their recycling to the plasma membrane. The endocytosis of membrane components is different from receptor-mediated endocytosis which is not affected in MLIV. Once the membrane macromolecules reach the lysosomes in MLIV they are normally catabolized and normally discharged. This may explain the heterogeneity of the stored materials in MLIV. The normal catabolism of macromolecules in the lysosomes is reflected in the minor deterioration in the clinical manifestations of these patients.

Cells, Cultured↗
PubMed1996

The molecular basis of Sanfilippo syndrome type B.

The Sanfilippo syndrome type B is a lysosomal storage disorder caused by deficiency of alpha-N-acetylglucosaminidase; it is characterized by profound mental deterioration in childhood and death in the second decade. For understanding the molecular genetics of the disease and for future development of DNA-based therapy, we have cloned the cDNA and gene encoding alpha-N-acetylglucosaminidase. Cloning started with purification of the bovine enzyme and use of a conserved oligonucleotide sequence to probe a human cDNA library. The cDNA sequence was found to encode a protein of 743 amino acids, with a 20- to 23-aa signal peptide immediately preceding the amino terminus of the tissue enzyme and with six potential N-glycosylation sites. The 8.5-kb gene (NAGLU), interrupted by 5 introns, was localized to the 5'-flanking sequence of a known gene, EDH17B, on chromosome 17q21. Five mutations were identified in cells of patients with Sanfilippo syndrome type B: 503del10, R297X, R626X, R643H, and R674H. The occurrence of a frameshift and a nonsense mutation in homozygous form confirms the identity of the NAGLU gene.

Acetylglucosaminidase↗
PubMed1996

[Genetic counseling for families at high cancer risk].

About 5-10% of the most common cancers, such as breast, colon and melanoma, result from mutations in inherited predisposition genes. Recently some of these genes have been mapped or even cloned. These advances in cancer genetics have made more precise genetic counseling possible for cancer patients and their families. In our clinic for specific genetic counseling 180 families with a history of cancer were seen during a 10-month period. In counseling sessions, the family history was confirmed and interpreted, personal risk was estimated and the availability of molecular genetic testing was presented. Blood samples for DNA testing were drawn from those with certain criteria who wished to be tested. Instructions for early detection were also given, depending on the personal risk of cancer as compared to that of the general population.

DNA↗
PubMed1995

Molecular basis of late infantile metachromatic leukodystrophy in the Habbanite Jews.

Late infantile metachromatic leukodystrophy (MLD) is a neurodegenerative disease, most commonly caused by the deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Late infantile MLD is frequent (1/75 live birth) in a small Jewish community which lived in Habban, isolated from the other Jewish populations. The gene coding for ARSA was sequenced in one of the Habbanite patients, who was found to be homozygous for an allele having three mutations. Two mutations are A to G transitions in the ARSA gene at positions 1788 and 2723, causing the loss of an N-glycosylation site and a polyadenylation signal, respectively. These mutations are characteristics for the ARSA pseudodeficiency (PD) allele, which in homozygozity is associated with low enzymatic activity, but does not cause disease. The third mutation, which occurred on the background of the PD allele, is a C to T transition at position 2119, predicting a substitution of proline-377 by leucine (P377L). Biosynthesis studies performed with cells expressing the ARSA cDNA into which this mutation was introduced demonstrated a severely reduced half-life of the mutant enzyme. Five of 10 patients from the Habbanite community could be studied and were homozygous for the P377L allele. These observations confirm the genealogical data which pointed to a common ancestor for all the carriers of MLD among the Habbanite Jews. In addition, the same mutation was demonstrated to be relatively frequent among the Yemenite Jews. The origin and the means by which the mutation spread between the two communities remain unknown.

Alleles↗
PubMed1995

Four novel mutations underlying mild or intermediate forms of alpha-L-iduronidase deficiency (MPS IS and MPS IH/S).

The alpha-L-iduronidase deficiency diseases (Mucopolysaccharidosis I) cover a spectrum of clinical severity ranging from the very severe (Hurler syndrome, MPS IH) through an intermediate (Hurler/Scheie syndrome, MPS IH/S) to a relatively mild form (Scheie syndrome, MPS IS). Numerous mutations of the gene encoding alpha-L-iduronidase (IDUA) are known in Hurler syndrome, but only three in the other disorders. We report on novel mutations of the IDUA gene in one patient with the Scheie syndrome and in three patients with the Hurler/Scheie syndrome. The novel mutations, all single base changes, encoded the substitutions R492P (Scheie), and X654G, P496L, and L490P (Hurler/Scheie). The L490P mutation was apparently homozygous, whereas each of the others was found in compound heterozygosity with a Hurler mutation. The deleterious nature of the mutations was confirmed by absence of enzyme activity upon transfection of the corresponding mutagenized cDNAs into Cos-1 cells. These results provide additional information for genotype-phenotype correlations.

Adult↗
PubMed1995

Down syndrome prevention program in a population with an older maternal age.

OBJECTIVE: To investigate the effect of a relatively high proportion of pregnant women 35 years and older on the efficacy of prenatal screening for Down syndrome. METHODS: We obtained information on normal and abnormal cytogenetic and maternal serum marker studies for 1990 and 1992 from all 11 public and two private cytogenetic laboratories operating in Israel. RESULTS: In the Jewish Israeli population, 16.2-17.1% of all pregnant women are at least 35 years old. Thus, prenatal testing of all pregnant women at least 35 years old could have identified 62.8-66.5% of all Down syndrome cases. Screening by maternal serum markers would classify 9.28% of pregnancies as being at high risk for Down syndrome (greater than 1:386 at birth). The percentage of Down syndrome cases detected prenatally increased from 78 of 147 (53%) to 123 of 163 (75%) as a result of the increased use of prenatal testing from 11.3% to 19.4% of all pregnancies in 1990 and 1992, respectively. CONCLUSIONS: In a population with a high proportion of mothers at least 35 years old, as in the Jewish population in Israel, screening by maternal serum markers instead of by maternal age alone would leave the Down syndrome detection rate unchanged, but would lower the amniocentesis rate from 16.2-17.1% to 9.28%. In addition to the reduction in the expected fetal loss as a result of post-amniocentesis spontaneous abortion, this policy would also pay the cost of maternal serum marker testing of the entire pregnant population.

Adult↗
PubMed1994

Mutation analysis of Jewish Hunter patients in Israel.

We have performed molecular and mutation analyses on 14 unrelated Israeli Hunter families and have identified the IDS mutation in 8 of them. Three unrelated Ashkenazi patients had the same previously reported mutation (1246 C-->T). Based on the haplotypes of the mutation-bearing chromosomes, we concluded that this is a recurrent mutation. In two patients, we identified a deletion spanning exons V-VII. Three novel mutations were observed in different patients: L410P, 717de14, and 244de13. In addition, the silent mutation (562 C-->T) was observed in one patient.

Amino Acid Sequence↗
PubMed1994

Late infantile metachromatic leukodystrophy in Israel.

Metachromatic Leukodystrophy (MLD) is a neurodegenerative disease in which the lysosomal enzyme, Aryl sulfatase A (ARSA) is deficient. The disease is inherited as an autosomal recessive trait and its frequency is estimated to be 1/40,000 live births. The gene of ARSA has been cloned and up to now eight mutations causing MLD have been reported. Another mutation, PD, leads to the deficiency of the enzyme in vitro (pseudodeficiency) without any known clinical effect. The PD mutation is frequent in all populations. In Israel, late infantile MLD was found to be very frequent in a small Jewish isolate, the Habbanite Jews (1/75 live births). The molecular analysis demonstrated that in the Habbanite population, the mutation occurred on an allele with the PD mutation. The loss of ARSA activity is due to a point mutation C > T leading to a change of proline to leucine. MLD is also frequent among Moslem Arabs in Jerusalem. The mutation is a transition G > A destroying the splice donor site of exon 2. This mutation has been reported in patients with the late infantile MLD from different ethnic groups. The Christian Arabs in Israel also have a high incidence of the disease (1/10,000 live births); the mutation in this population is still unknown. Knowledge of the different mutations causing MLD in these defined populations will allow a carrier screening program to be carried out and prevent the birth of additional affected children.

Child↗
PubMed1994

Hunter syndrome among Jews in Israel.

Hunter syndrome (mucopolysaccharidosis II) is an X-linked lysosomal storage disorder caused by the deficiency of iduronate sulfatase (IDS), the gene of which is located at Xq28. A relatively high frequency of Hunter disease among Ashkenazi and Moroccan Jews in Israel was observed. Genetic analysis of the patients with Hunter disease in these ethnic groups indicated the absence of new mutations and a two-fold excess of individuals with the mutant allele over non carriers. This unusual phenomenon is unique to these ethnic groups and is suggestive of a prenatal selection process favoring the Hunter allele. Studies of the IDS gene structure and its flanking region are performed with the aim of detecting the mutations causing the disease in these patients and thus develop the most accurate diagnostic procedure for carrier identification among female relatives in these families. Furthermore, these studies are also aimed at identifying the unique molecular structure in the IDS gene or its flanking region which is the basis for the selection process. RFLP analysis using the cDNA gene (pc2S15) and DNA probes closely linked to the IDS gene, as well as the study of CA repeats in a closely linked region, indicated the absence of common haplotypes among Ashkenazi or Moroccan patients, excluding a linkage disequilibrium between a putative advantageous linked gene to the Hunter mutation in our patients. Studies of the IDS gene indicated a partial deletion in two patients while the other 12 patients had an apparent intact gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗
PubMed1994

Prenatal testing for Down syndrome in the Jewish and non-Jewish populations in Israel.

The present work evaluated the efficacy of a prenatal diagnosis program in which amniocentesis and chorionic villus sampling were offered free of charge to all pregnant women in Israel aged > or = 37 years. The number of Down syndrome (DS) live births that occurred during the period of the program (1978-92) was correlated to the prevalence of old maternal age (> 35 years) and the utilization of prenatal test in the Jewish and non-Jewish populations in 1990 and 1992. It was noted that in the Jewish population, there was a slight increase in the DS live birth rate, from 1.05 in 1978, to 1.37 DS cases/1,000 live births in 1987, which corresponded to an increase in the prevalence of older pregnant women, from 8.0% in 1978 to 14.8% in 1987. Thereafter, however, there was a continuous decline, to 0.71 DS cases/1,000 live births in 1992, as a result of increased acceptance of prenatal testing by women > or = 37 years (67%) and, recently, also by younger women (from 5.6% in 1990 to 14% in 1992). In the non-Jewish population, there has been a very low acceptance rate of prenatal testing (23.3-16.1% in women > or = 37 years and 0.36-0.63% in women < 37 years). As a result, a very low prenatal detection rate (8-16% of all DS cases) and a high prevalence of DS live births (1.4 cases/1,000 live births) were observed. We suggest that a unique genetic counseling approach is required in the non-Jewish population to improve prenatal DS prevention in Israel.

Adult↗
PubMed1993

Combined enzymatic and linkage analysis for heterozygote detection in Hunter syndrome: identification of an apparent case of germinal mosaicism.

Hunter syndrome is an X-linked recessive disorder. Determination of heterozygotes is of vital importance in genetic counselling. We describe the DNA linkage analysis in 6 Hunter syndrome families and compare it to previous results based on a serum assay for IDS activity. Our results confirm the reliability of the serum assay. The serum test correctly detected 11/12 of the 1st degree relatives tested by the serum assay (6/7 carriers and 5/5 non-carriers). The only case with an apparent false negative result in the serum test was a daughter of a "probable heterozygote" whose serum test was also negative. We suggest that in this family the mother represented a case of germinal mosaicism and her daughter, based on the serum test, was not a carrier. If our interpretation is correct, then the apparent false negative results were correct. It is concluded that in families where the mutation is not known and DNA analysis is not possible due to the lack of informative RFLPs or due to the lack of DNA samples on key individuals, as well as in sporadic cases, the serum test should be applied as an alternative option for heterozygote detection.

Blotting, Southern↗
PubMed1993

Mucolipidosis type IV: a mild form with late onset.

A 16-year-old girl is presented with mild clinical manifestations and late onset of mucolipidosis type IV (MLIV). The patient, an Ashkenazi Jew, has had minor motor difficulties and mild psychological disturbances since early childhood. Her vision began deteriorating at 12 years of age, due to bilateral corneal opacities and retinal degeneration. At present she attends a regular high school, although she is slow and scholastic achievements are lower than average. Electron microscopic examination and biochemical studies were typical for MLIV, namely, abnormal ganglioside retention and typical pattern of phospholipids accumulation. This very mild presentation of MLIV suggests a broader spectrum of heterogeneity of this disorder and raises the possibility that MLIV, at least among Ashkenazi Jews, might be more frequent than estimated hitherto, due to undiagnosed mild patients.

Adolescent↗
PubMed1993

Screening for carriers of Tay-Sachs disease in the ultraorthodox Ashkenazi Jewish community in Israel.

A screening program for the detection of Tay-Sachs disease (TSD) carriers in the ultra Orthodox community of Ashkenazi Jews has operated in Israel since 1986. The purpose of this program is the prevention of marriages of 2 heterozygotes. The screened individuals are mostly couples in the engagement process or students in religious high schools. Two mandatory requirements guide this program. First, anonymity of the tested individuals who are identified only by code numbers; second completion of the test results of couples in the engagement process within a few days. The screening program is performed by the determination of hexosaminidase A (Hex A) activity in serum which is repeated in serum and leukocyte extracts in couples where both partners were found in the heterozygote range in the initial tests. The minimal carrier frequency was estimated to be 1:26 or higher, which is higher then in the general Jewish Ashkenazi population. This higher carrier frequency apparently stems from the fact that most members of this community originate from central Europe where the TSD carrier frequency was previously reported to be the highest in the Ashkenazi population. Since the beginning of the screening program no TSD child has been born to newlywed couples of this community in Israel.

Anonymous Testing↗
PubMed1993

Inhibition of protein kinase C activity in mucolipidosis type-4: a model for a new pathogenetic mechanism in inborn errors of metabolism.

Inhibition of protein kinase C [PK-C] activity by sphingosine and its derivatives has been suggested to play a role in the pathogenesis of sphingolipidoses. In the present study, PK-C activity and PK-C-mediated phosphorylation of endogenous substrates were studied in skin fibroblasts from patients with mucolipidosis type 4 [ML-4], in which there is accumulation of the phospholipids phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine as well as gangliosides. Cytosolic PK-C activity in 5 ML-4 cell lines was comparable to that in control cells. PK-C activity in the particulate fraction of these cells was 84 +/- 14 pmol 32P/mg protein per min compared with 267 +/- 26 in control cells. Increasing the concentrations of the activating lipids in the reaction mixture did not enhance PK-C activity in ML-4 cells, suggesting a non-competitive inhibition of the kinase. Following partial purification of the enzyme from the particulate fraction PK-C activity increased to 288 +/- 14 and 339 +/- 12 pmol 32P/mg protein per min in ML-4 and control cells, respectively. The phosphorylation pattern of endogenous substrates in the particulate fraction of ML-4 cells differed from that in control cells both in the absence and in the presence of calcium and activating lipids. We suggest that PK-C may be involved in the pathogenesis of sphingolipidoses and that this may represent an example for a new type of pathogenetic mechanisms in inborn errors of metabolism.

Humans↗
PubMed1993

Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area.

The mutations underlying Hurler syndrome (mucopolysaccharidosis IH) in Druze and Muslim Israeli Arab patients have been characterized. Four alleles were identified, using a combination of (a) PCR amplification of reverse-transcribed RNA or genomic DNA segments, (b) cycle sequencing of PCR products, and (c) restriction-enzyme analysis. One allele has two amino acid substitutions, Gly409-->Arg in exon 9 and Ter-->Cys in exon 14. The other three alleles have mutations in exon 2 (Tyr64-->Ter), exon 7 (Gln310-->Ter), or exon 8 (Thr366-->Pro). Transfection of mutagenized cDNAs into Cos-1 cells showed that two missense mutations, Thr366-->Pro and Ter-->Cys, permitted the expression of only trace amounts of alpha-L-iduronidase activity, whereas Gly409-->Arg permitted the expression of 60% as much enzyme as did the normal cDNA. The nonsense mutations were associated with abnormalities of RNA processing: (1) both a very low level of mRNA and skipping of exon 2 for Tyr64-->Ter and (2) utilization of a cryptic splice site for Gln310-->Ter. In all instances, the probands were found homozygous, and the parents heterozygous, for the mutant alleles, as anticipated from the consanguinity in each family. The two-mutation allele was identified in a family from Gaza; the other three alleles were found in seven families, five of them Druze, residing in a very small area of northern Israel. Since such clustering suggests a classic founder effect, the presence of three mutant alleles of the IDUA gene was unexpected.

Alleles↗