Anat Blumenfeld

Frequent loss of chromosome 14 in atypical and malignant meningioma : identification of a putative 'tumor progression' locus

Formation of meningiomas has been associated with the loss of genetic material on chromosome 22. To approach the additional chromosomal events that underlie progression of these tumors to malignancy, we have examined several other chromosomal regions for loss of heterozygosity (LOH) in these tumors. Fifty-eight tumors, comprising 43 benign meningiomas, 11 atypical meningiomas and four malignant meningiomas, were examined. While the loss of chromosome 22 was seen in approximately half of all these tumors, regardless of their malignancy, the most frequent chromosomal losses observed in the malignant and atypical tumors were on the long arm of chromosome 14. Thirty-nine tumors were informative for at least one of the three markers on chromosome 14 that we tested. Of these, 7/14 malignant and atypical tumors showed LOH in contrast to only 1/25 benign tumors. Other loci that showed LOH in malignant tumors, although at a much lower frequency, were on chromosomes 17p and 1p. The high frequency of LOH for loci on chromosome 14q in atypical and malignant tumors suggests the presence of a tumor progression gene at this locus. In one of the malignant meningiomas heterozygosity was lost at D14S13 and D14S16 but retained at the proximal marker D14S43 as well as the more distal marker D14S23. This suggests that an interstitial deletion occurred in this tumor which should be useful for further refining the position of the putative tumor progression locus.

Bone mineral metabolism in adults with β-thalassaemia major and intermedia

Bone disease is an important cause of morbidity in older patients with β‐thalassaemia major and intermedia. We studied 27 women and 23 men with β‐thalassaemia major (37) and intermedia (13) whose mean age was 32·3 ± 9·7 years. Bone mineral density (BMD) of the lumbar spine, femoral neck and distal radius was determined by dual‐energy X‐ray absorbiometry (DXA). The longitudinal change in BMD over a mean of 5·6 years was determined in 19 patients. Serum 25‐hydroxyvitamin D, insulin growth factor‐1 (IGF‐1), bone formation markers bone‐alkaline phosphatase, osteocalcin and the resorption marker urinary N‐telopeptide cross‐linked type 1 collagen (NTx) were determined. The BsmI vitamin D receptor (VDR) gene polymorphism was analysed. Reduced BMD (Z‐score < −2) was present in 89%, 62% and 73% of patients in the spine, hip and radius respectively. Vitamin D deficiency was found in 62%, decreased IGF‐1 in 72% and increased urinary NTx in 84% of patients. Serum IGF‐1 correlated with spine and hip BMD (r = 0·4, r = 0·39, P < 0·01 respectively), and NTx correlated with the hip BMD Z‐score (r = 0·35 P < 0·05). The mean annual percentage change in spine BMD was −1·36%. Patients with the VDR BB genotype had lower spine BMD than patients with the bb genotype. In conclusion, bone loss continues in adult thalassaemia patients and is associated with increased bone resorption and decreased IGF‐1. The BsmI VDR gene polymorphism is associated with osteopenia in thalassaemia.

Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype.

Identification of the first non-Jewish mutation in familial Dysautonomia

Familial Dysautonomia is an autosomal recessive disease with a remarkably high carrier frequency in the Ashkenazi Jewish population. It has recently been estimated that as many as 1 in 27 Ashkenazi Jews is a carrier of FD. The FD gene has been identified as IKBKAP, and two disease‐causing mutations have been identified. The most common mutation, which is present on 99.5% of all FD chromosomes, is an intronic splice site mutation that results in tissue‐specific skipping of exon 20. The second mutation, R696P, is a missense mutation that has been identified in 4 unrelated patients heterozygous for the major splice mutation. Interestingly, despite the fact that FD is a recessive disease, normal mRNA and protein are expressed in patient cells. To date, the diagnosis of FD has been limited to individuals of Ashkenazi Jewish descent and identification of the gene has led to widespread diagnostic and carrier testing in this population. In this report, we describe the first non‐Jewish IKBKAP mutation, a proline to leucine missense mutation in exon 26, P914L. This mutation is of particular significance because it was identified in a patient who lacks one of the cardinal diagnostic criteria for the disease–pure Ashkenazi Jewish ancestry. In light of this fact, the diagnostic criteria for FD must be expanded. Furthermore, in order to ensure carrier identification in all ethnicities, this mutation must now be considered when screening for FD.

The C677T Mutation in the Methylenetetrahydrofolate Reductase (MTHFR) Gene and Vascular Dementia

OBJECTIVE: To determine the association between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular dementia in Ashkenazi and non‐Ashkenazi Jews.

Ethnic differences in the frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in healthy Israeli populations.

Hyperhomocysteinemia is an independent risk factor for arteriosclerotic vascular disease. It can result from deficiencies of co-factors required for homocysteine metabolism and/or from genetic disorders of its metabolism. The association between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular disease is controversial, and may be affected by ethnic origin. A unique feature of the Israeli population is its ethnic diversity. The aim of this study was to study the frequency of the C677T MTHFR mutation in healthy Israeli ethnic groups. The frequency of the mutation was determined in 897 young healthy Jewish and Muslim Arab Israelis of eight different ethnic groups. Marked ethnic differences in the frequency of mutant homozygotes were found, ranging from 2% in Yemenite Jews, 4% in Sephardic Jews, 9% in Oriental Jews, 10% in Muslim Arabs, 16% in North African Jews, and 19% in Ashkenazi Jews. The frequency of mutant homozygotes was significantly higher in Ashkenazi Jews compared to Yemenites Oriental Jews, Sephardic Jews, and Muslim Arabs (chi2 = 12.35p < 0.001, chi2 = 8.17p = 0.004, chi2 = 6.04p = 0.01, chi2 = 6.54 p = 0.01, respectively). Our findings demonstrate the need for matching ethnic background in patients and controls when studying the association between the C677T MTHFR mutation and any disease.

Exclusion of p75NGFR and other candidate genes in a family with hereditary sensory neuropathy Type II

&NA; Hereditary sensory neuropathy Type II (HSN II) is an autosomal recessive disorder characterized by the loss of peripheral sensory modalities in individuals with otherwise normal development. Patients with HSN II often have chronic ulceration of the fingers and toes, autoamputation of the distal phalanges, and neuropathic joint degeneration associated with loss of pain sensation. Recent descriptions of a similar phenotype in mice carrying a targeted mutation in the low affinity nerve growth factor receptor, p75NGFR, suggested the possibility that mutations in this gene or other members of the nerve growth factor (NGF) family of genes and their receptors might be responsible for this human disorder. In this study candidate genes were evaluated by their inheritance pattern in two sisters affected with HSN II, their unaffected sister and mother in a consanguineous family. The segregation of polymorphic alleles at and around loci for p75NGFR, TRKA, TRKB, BDNF, and familial dysautonomia (another hereditary sensory neuropathy having features in common with HSN II) virtually excluded these genes as the cause of HSN II in this family. Further evaluation of loci for other neurotrophic factors and their receptors, which will be possible when mapping information on their loci becomes available, may permit the identification of the gene responsible for HSN II.

Cloning, mapping, and expression of a novel brain-specific transcript in the Familial Dysautonomia candidate region on Chromosome 9q31

Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts, USA Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Laboratory of Genetics, National Institute of Mental Health/National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA Unit for Development of Molecular Biology and Genetic Engineering, Hadassah University Hospital, Jerusalem, Israel Department of Pediatrics, New York University Medical School, New York, New York, USA Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel

Exclusion of familial dysautonomia from more than 60% of the genome

Familial dysautonomia (FD) is a recessive neurological disorder that affects the development of the sensory and autonomic nervous system. The gene defect appears to be limited to the Ashkenazi Jewish population, where the carrier frequency is 1 in 30. One hundred and ninety-one marker loci representing all autosomes were tested for linkage with the FD genetic defect in 23 families. A combination of pairwise and multipoint analyses excluded the FD gene from at least 60% of the autosomal genome. The program EXCLUDE predicted regions of chromosomes 2, 4, 5q, 9, or 10 as the most promising locations for future analyses.

The BsmI Vitamin D Receptor Gene Polymorphism in Israeli Populations and in Perimenopausal and Osteoporotic Ashkenazi Women

Background: The association between vitamin D receptor (VDR) gene polymorphisms and bone mineral density (BMD) is controversial, and may be effected by ethnic ancestry and age. Aims: To determine the distribution of the BsmI VDR gene polymorphism in healthy Israeli populations, and to study its association with BMD in perimenopausal and osteoporotic Ashkenazi women. Methods: Allele and genotype frequencies of the VDR gene defined by BsmI restriction site were determined in 634 healthy Israelis of seven ethnic groups, 90 Ashkenazi perimenopausal women and in 75 Ashkenazi osteoporotic women. Genotype-related differences in spinal and femoral neck BMD were determined in Ashkenazi perimenopausal women. Allele and genotype frequencies in Ashkenazi osteoporotic women were compared with Ashkenazi controls. Results: The frequency of the BB genotype was higher in Yemenites compared with Ashkenazi and Libyan Jews (23, 11 and 8%, respectively, p < 0.05), and lower in Ashkenazi compared with Iraqi and Persian Jews (11, 20 and 21%, respectively, p = 0.05). BMD did not vary by genotype in perimenopausal women, nor were there differences in the frequencies of the B allele or the BB genotype in osteoporotic women compared with controls. Conclusions: There is ethnic variability in the frequency of the BsmI VDR gene polymorphism. In Ashkenazi perimenopausal and osteoporotic women this polymorphism is not associated with BMD.