Ashkenazi Patients Research Articles

Comprehensive Arrayed Primer Extension Array for the Detection of 59 Sequence Variants in 15 Conditions Prevalent Among the (Ashkenazi) Jewish Population

In the Ashkenazi Jewish population, serious and lethal genetic conditions occur with relatively high frequency. A single test that encompasses the majority of population-specific mutations is not currently available. For comprehensive carrier screening and molecular diagnostic purposes, we developed a population-specific and inclusive microarray. The arrayed primer extension genotyping microarray carries 59 sequence variant detection sites, of which 53 are detectable bi-directionally. These sites represent the most common variants in Tay-Sachs disease, Bloom syndrome, Canavan disease, Niemann-Pick A, familial dysautonomia, torsion dystonia, mucolipidosis type IV, Fanconi anemia, Gaucher disease, factor XI deficiency, glycogen storage disease type 1a, maple syrup urine disease, nonsyndromic sensorineural hearing loss, familial Mediterranean fever, and glycogen storage disease type III. Several mutations in the selected disorders that are not prevalent per se in the Ashkenazi Jewish populations, as well pseudodeficiency alleles, are also included in the array. The initial technical evaluation of this microarray demonstrates that it is comprehensive, robust, sensitive, specific, and easily modifiable. This cost-effective array is based on a diversely applied platform technology and is suitable for both carrier screening and disease detection in Ashkenazi and Sephardic Jewish populations.

The Y152X MC1R gene mutation: occurrence in ethnically diverse Jewish malignant melanoma patients

MC1R sequence variants are associated with malignant melanoma risk, and most commonly are missense mutations. Few (n=9) truncating mutations have been described in this gene as predisposing to malignant melanoma. In this study, three Jewish individuals were found to harbor an identical truncating MC1R mutation--Y152X: an Ashkenazi patient with two malignant melanomas, a non-Ashkenazi malignant melanoma patient with familial malignant melanoma and her asymptomatic mother. Both malignant melanoma patients carried additional, seemingly pathogenic MC1R variants. Haplotype analysis revealed that all three mutation carriers shared the same haplotype. This sequence variant was previously described in ethnically diverse, non-Jewish individuals and in all likelihood represents an error-prone domain that, in conjunction with other genetic and environmental factors, increases malignant melanoma risk.

Mutation screening and association study of the candidate prostate cancer susceptibility genesMSR1,PTEN, andKLF6

MSR1, PTEN, and KLF6 have been implicated as candidate susceptibility genes for prostate tumorigenesis. Three hundred Jewish prostate cancer patients were screened for alterations in these genes. MSR1 was conserved in all patients. PTEN screening revealed a novel missense mutation and a silent change. Five KLF6 alterations were detected in 17 patients, including Q160X, the only nonsense KLF6 germline mutation described to date in a cancer patient. The KLF6 IVS1-27G>A polymorphism, recently associated with prostate cancer risk, was detected in 11.9% of the patients and 17.3% of the controls (P = 0.043). IVS1-27A allele frequency was significantly lower in prostate cancer patients (P = 0.030), specifically in Ashkenazi patients (P = 0.047) compared to controls. We found no evidence that MSR1 and PTEN germline mutations are associated with prostate cancer risk in Jews. The negative association between KLF6 IVS1-27A and prostate cancer risk supports a population-specific effect of susceptibility alleles in prostate tumorigenesis.

RNASELMutation Screening and Association Study in Ashkenazi and Non-Ashkenazi Prostate Cancer Patients

Epidemiologic and genetic studies support the considerable effect of heritable factors on prostate tumorigenesis, although to date, no unequivocal susceptibility gene has been identified. The extensive study of RNASEL in prostate cancer patients worldwide has yielded conflicting results. We reevaluated the role of the RNASEL 471delAAAG Ashkenazi founder mutation in 1,642 Ashkenazi patients with prostate, bladder, breast/ovarian, and colon cancers; Ashkenazi controls; and in non-Ashkenazi prostate cancer patients and controls. The entire RNASEL coding sequence was also screened using denaturing high-performance liquid chromatography and multiplex ligation-dependent probe amplification for possible sequence variations or copy number changes in a population of prostate cancer patients. The 471delAAAG mutation was detected in 2.4% of the Ashkenazi prostate cancer patients; in 1.9% of patients with bladder, breast/ovarian, and colon cancers; and in 2.0% of the Ashkenazi controls. Seven additional variants were detected in RNASEL, including a novel potentially pathogenic splice site mutation, IVS5+1delG, although none were associated with increased prostate cancer risk. Multiplex ligation-dependent probe amplification analysis showed two RNASEL gene copies in all 300 prostate cancer patients tested. We estimated that the RNASEL 471delAAAG founder mutation, which was detected in 2% of the Ashkenazi Jews, originated between the 2nd and 5th centuries A.D., compared with the less frequent (1%) BRCA1 185delAG founder mutation, which originated hundreds of years earlier. Taken together, our analysis does not support a role for the RNASEL 471delAAAG Ashkenazi mutation nor for the other alterations detected in RNASEL in prostate cancer risk in Jewish men.

Mutations in the glucocerebrosidase gene and Parkinson disease: Phenotype–genotype correlation

Mutations in the glucocerebrosidase (GBA) gene have been recently identified as contributory to Parkinson disease (PD) in Ashkenazi Jews. In the present study, the clinical characteristics of Ashkenazi patients with PD with GBA mutations (n = 40) were compared to those of Ashkenazi patients with PD without any known GBA mutation (n = 108). The overall clinical manifestations and age at disease onset did not differ in patients with GBA mutations compared to patients without mutations.

Transmission disequilibrium and haplotype analyses of the G72/G30 locus: Suggestive linkage to schizophrenia in Palestinian Arabs living in the North of Israel

Association of the G72/G30 locus with schizophrenia was recently reported in French Canadian, Russian, and Ashkenazi populations using case-control studies. In the present study we hypothesize the existence of a G72/G30 risk allele over-transmitted to affected sibs in Palestinian Arab families. A total of 223 Palestinian Arab families that included an affected offspring and parents were genotyped with 11 SNPs encompassing the G72/G30 genes. The families were recruited from three regions of Israel: 56 from the North (Afula), 136 from the central hill region (Bethlehem, Palestinian Authority), and 31 from the South (Beersheva). Individual SNP analyses disclosed a risk allele in SNP rs3916970 by both haplotype relative risk (HRR: chi(2) = 5.59, P = 0.018) and transmission disequilibrium test (TDT: chi(2) = 6.03, P = 0.014) in the Afula families. Follow-up multilocus analysis using family-based association tests (FBAT: z = 2.197, P = 0.028) exposed the adjacent haplotype. SNP rs3916970 is located about 8 kb from the linkage disequilibrium block that was reported to be associated with schizophrenia in Ashkenazi Jews. Excess of similar haplotypes of this region was observed in the Palestinian Arabs and the Ashkenazi patients. These data suggest a common risk factor for schizophrenia susceptibility in the G72/G30 locus among Ashkenazi Jews and Palestinian Arabs. The results strengthen previous reports on the role of this locus in the etiology of schizophrenia.

Genetic Analyses in Consecutive Israeli Jewish Colorectal Cancer Patients

Two APC germline mutations, E1317Q and I1307K, have been linked to colorectal cancer (CRC) risk. Whereas the I1307K variant is almost exclusively encountered in (Ashkenazi) Jews, E1317Q is not restricted to certain ethnic populations. Data on its contribution to CRC risk in Jewish patients are sparse. To assess the contribution of E1317Q to CRC development in the Jewish population. A total of 538 consecutive Israeli Jewish CRC patients and 440 controls were genotyped for E1317Q. In addition, the rate of the I1307K APC missense mutation and the two predominant Jewish mutations in hMSH2, A636P, and 324delCA, associated with hereditary nonpolyposis colon cancer (HNPCC), were determined. The E13117Q missense mutation was detected in 6/538 (1%) of CRC patients and 5/440 (1%) of controls. The I1307K variant was found in 8% of all patients and in 11% (35/322) of patients of Ashkenazi Jewish descent. Carriers and noncarrier CRC patients did not differ in age of onset or associated colonic adenomatous polyps. The carrier rate among controls was 5% among Ashkenazim and 1.6% among non-Ashkenazi individuals. The 324delCA hMSH2 mutation was not observed in this cohort, and 4 of 322 Ashkenazi patients (1.2%) displayed the A636P mutation. In Jewish CRC patients the E1317Q variant plays little if any role in colorectal cancer susceptibility and genetic testing for this variant is not warranted. The I1307K mutation is associated with a moderate excess risk for CRC, but age of onset seems not to be earlier and this variant is not associated with a multiple colonic polyp phenotype. Founder mutations in hMSH2 are rare in consecutive CRC patients.

Genotype phenotype correlations in Israeli colorectal cancer patients

While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli CRC patients were genotyped using SNPs from within candidate genes: APC, beta-Catenin, K-RAS, DCC, P16, PTEN, RB1, P15, APOE, ERCC2, P53, MTHFR and hMSH2. Genotyping of consecutive, unselected colorectal cancer patients was done mostly by utilizing the MassARRAY technology (Sequenom) and to a lesser extent DGGE, ARMS and direct DNA sequencing. Correlation of genotypes with specific phenotypic features was carried out for all patients and separately for the Ashkenazim. Overall, 456 patients were analyzed, the majority (64.25%) being of Ashkenazi origin; mean age at diagnosis was 65.6 +/- 14 (range 25-90 years), and the mean follow-up was 4.7 +/- 0.28 (range 0-30 years). Statistically significant associations were noted between SNPs in beta-catenin and APOE and a positive family history of cancer (beta-catenin: p=0.034, APOE: p=0.033); tumor location and a DCC SNP (p=0.038) and the P53 R72P mutation and survival (p=0.0336). In Ashkenazi patients, ERCC2 and MTHFR genes' SNPs were associated with age at diagnosis (ERCC2: p=0.025, MTHFR: p=0.0005); a P53 polymorphism, APOE and Rb SNPs with a family history of cancer (P53 p=0.034;APOE p=0.04, Rb p= 0.022); DCC SNP with tumor location (p=0.014); and p15 SNP with tumor grade (p=0.032). This preliminary study shows that genetic factors play a role in determining CRC phenotypic features and that a larger cohort with longer follow-up is clearly needed.

The BsmI Vitamin D Receptor Gene Polymorphism Is Associated with Ulcerative Colitis in Jewish Ashkenazi Patients

Susceptibility to inflammatory bowel disease (IBD) has a strong genetic component. The vitamin D receptor (VDR) gene maps to a region on chromosome 12 shown to be associated with IBD in some studies. In this case-control study we determined the association between the BsmI VDR gene polymorphism and IBD in patients with Crohn's disease (CD) and ulcerative colits (UC). Three hundred seventy-nine Jewish Israeli patients with IBD, 228 with CD (129 Ashkenazi and 99 non-Ashkenazi), and 151 patients with UC (72 Ashkenazi, 79 non-Ashkenazi) were studied. The control group included 495 healthy blood donors (352 non-Ashkenazi and 143 Ashkenazi). All subjects were genotyped for the BsmI VDR gene polymorphism. The frequency of the BB genotype was higher in Ashkenazi patients with UC compared to Ashkenazi controls (0.21 vs. 0.11, p = 0.042, odds ratio 2.27, 95% confidence interval [CI] 1.06-4.9). There were no differences in the prevalence of the BB genotype or the B allele between ethnically matched patients with CD and UC. Nor were there differences in the BB genotype or B allele frequencies between CD patients and ethnically matched controls. The BsmI VDR gene polymorphism is associated with increased susceptibility to UC in Israeli Ashkenazi patients with UC.

NOD2/CARD15 mutation analysis and genotype-phenotype correlation in Jewish pediatric patients compared with adults with Crohn's disease

Objectives The allelic variants in the NOD2/CARD15 gene G908R, R702W, and 1007fs are strongly and independently associated with susceptibility to Crohn's disease (CD). Our aim was to compare the NOD2/CARD15 genotype and the genotype-phenotype correlation in Jewish pediatric patients with CD (≤16 years of age) with older patients with CD. Study design Carrier frequencies of the three variants were determined in 67 children and 144 adults with CD. Variants were detected by using allele-specific polymerase chain reaction and restriction enzyme digestion assay. Demographic and phenotypic characterizations of the patients were determined. Results The carrier rate of the three NOD2/CARD15-associated variants was 51.5% in children and 37.5% in adults ( P = .07). The most prevalent allele variant was G908R (allele frequency 18% in children, 11% in adults; P = .063). Young Ashkenazi patients had the highest allele frequency of G908R, and higher than Ashkenazi adults: 25% and 9%, respectively ( P = .003). Children had more family history of inflammatory bowel disease and more inflammatory-type disease, with no relation to variant allele carriage. Conclusions G908R allele-variant of the NOD2/CARD15 gene is closely related with the appearance of CD at a young age in Jewish Ashkenazi patients.

P0606 NOD2 /CARD15 MUTATION ANALYSIS AND GENOTYPE-PHENOTYPE CORRELATION IN JEWISH PEDIATRIC PATIENTS WITH CROHN???S DISEASE

Introduction: The allelic variants in the NOD2/CARD15 gene G908R, R702W and 1007fs are strongly and independently associated with susceptibility to Crohn’s disease (CD). Patients diagnosed in childhood tend to have a separate and more severe phenotype of CD. Our aim was to compare the NOD2/CARD15 genotype and the genotype-phenotype correlation in pediatric Jewish CD patients (< 16 years) to older CD patients. Methods: Carrier frequency of the three variants was determined in 67 children and 144 adults with CD. Variants were detected using allele-specific PCR and restriction enzyme digestion assay. The SNP5-JW1 combination was analyzed separately, excluding the inluence of the other three CARD15 variants. Demographic and phenotypic characterizations of the patients were determined Results: The mean age at diagnosis was 11.9±3.2 years in children and 28.5±11.8 years in adults; 61% and 55% respectively were males. The proportion of the Jewish subpopulations (Ashkenazi, Sephardic and mixed) was similar in both groups, as was the extent of disease. The carrier rate of the three NOD2/CARD15-associated variants was 51.5% in children and 37.5% in adults (p=0.07). The most prevalent allele variant was G908R (allele frequency 18% in children, 11% in adults, p=0.063). Young Ashkenazi patients had the highest allele frequency of G908R, and higher than Ashkenazi adults: 18% and 11% respectively (p=0.003). Children had more family history of CD than adults (37.9% vs. 23.6%, p=0.046) and more inflammatory-type disease (66.7% vs. 48.3%, p=0.046), with no relation to variant allele carriage. Conclusion: G908R allele-variant of the NOD2/CARD15 gene is closely related with the appearance of CD at young age in Jewish Ashkenazi patients.

Prevalence of myotonic dystrophy in Israeli Jewish communities: inter-community variation and founder premutations.

In a comprehensive epidemiological survey among Jews living in Israel, the average prevalence of myotonic dystrophy (DM) was 15.7/10(5) (1 case in 6369) with intercommunity variations; the Ashkenazi Jews had the lowest rate, 5.7/10(5) (1 case in 17544) as compared to the rate in the Sephardim/Oriental Jews 20/10(5) (1 case in 5000) and the in the Yemenite Jews 47.3/10(5) (1 case in 2114). The rate of unrelated DM-sibships per 10(6) people of each community was used as an estimate of the transition rate from stable to unstable DMPK-(CTG)(n) alleles assuming that each transition is a beginning of a new DM sibship. This study indicated that the difference in the incidence of DM is a result of higher mutation rate in the non-Ashkenazi Jews (>50/10(6)) as compared to the rate in the Ashkenazi Jews (16.3/10(6)). The intragenic haplotype of the DM alleles was the same as that of the DM in many populations all over the world. However, two DM closely linked markers D19S207 and D19S112 were in linkage disequilibrium with the DM mutation in patients of Yemenite and Moroccan (the largest subgroup in the Sephardim Jews) extractions and not in the Ashkenazi patients. This observation indicated a common ancestral origin for the DM premutation in patients of the same ethnic origin. We concluded that the difference in the prevalence of DM among the Jewish communities is a consequence of founder premutations in the non-Ashkenazi Jewish communities.

Differences of NOD2 (CARD15) genotype and phenotype among ashkenazi and sepahardic jews with Crohns disease: Preliminary evidence indicating higher carrier rate in the Ashkenazi patients

Differences of NOD2 (CARD15) genotype and phenotype among ashkenazi and sepahardic jews with Crohns disease: Preliminary evidence indicating higher carrier rate in the Ashkenazi patients

Hexosaminidase A deficiency is an uncommon cause of a syndrome mimicking amyotrophic lateral sclerosis.

Patients with adult hexosaminidase A (Hex A) deficiency may have clinical manifestations similar to amyotrophic lateral sclerosis (ALS). Mutations in the hexosaminidase A (HEXA) gene are common in the Jewish Ashkenazi population in Israel. Serum samples of 115 Israeli patients with sporadic ALS were screened for enzymatic activity to detect "enzyme-based carriers." Fifteen samples with low (< 50%) enzymatic activity were subjected to mutation analysis, which included the two common mutations in the HEXA gene among Ashkenazi Jews (+1278TATC and IVS12+1G-->C). Three "enzymatic carrier" patients of Moroccan origin were checked for two additional mutations (DeltaF304/305 and Arg170-->Gln), specific to this ethnic group. Two "enzymatic carrier" patients of Iraqi origin were analyzed for the mutation Gly250-->Val, specific to this population. The mutation Gly 269-->Ser was screened in carriers of Ashkenazi origin only (n = 10). The only abnormalities found were heterozygous +1278TATC mutations in two Ashkenazi patients. Their clinical presentation was not different from that usually encountered in ALS. The frequency of mutations in the HEXA gene among Israeli ALS patients was not higher than in the healthy Israeli population. Therefore, Hex A deficiency seems to be a very unlikely cause of an ALS-mimic syndrome.

Clinical and demographic characterization of Jewish Crohn's disease patients in Israel.

Crohn's disease (CD) is a chronic transmural inflammatory disease of unknown etiology. Genetic background may influence the nature of disease. The Jewish population in Israel is composed of Ashkenazi and Sephardic Jews, who differ in their genetic background. Previous studies have reported that the prevalence of CD in Sephardic Jews is lower than in Ashkenazi Jews; however, no information is available regarding disease characteristics in these patient populations. To assess the demographic and clinical characteristics of CD in Israeli Jewish patients. We studied 189 CD patients who were observed in our department. Demographic and clinical data were collected and analyzed. Forty-eight percent of the patients had ileum-only disease. Fistulizing disease was more frequently seen in ileocolonic than in ileal ( p= 0.04) or colonic ( p= 0.01) disease, whereas strictures occurred more often in ileal than in colonic disease (22% and 3%, respectively, p= 0.007). No association was found between current smoking and disease severity. Sephardic patients more frequently had extraintestinal disease than did Ashkenazi patients (35% vs. 17%, respectively, = 0.019). Jewish Israeli patients show a predilection for ileum-only disease. Disease severity appears not to be influenced by smoking. These differences in disease behavior may be related to genetic factors.

Serum Creatine Kinase Levels in Untreated Hospitalized Adolescents During Acute Psychosis

Psychosis-associated creatine kinase (CK)-emia (PACK) is a common and pronounced laboratory abnormality that accompanies adult psychotic conditions. Adult PACK is a relatively consistent individual trait. The authors investigated whether psychotic adolescents also present with such PACK characteristics. Participants were 127 newly admitted, drug-free, psychotic Israeli adolescents. Measures were baseline psychotic severity, serum creatine kinase (CK0), lactate dehydrogenase (LDH0), glutamate oxaloacetate transaminase (SGOT0), white blood cell count (WBC0), urine myoglobulin, and the repeated CK (RepCK) measurements taken during recurrent psychotic episodes. Schizophrenia was the prevalent diagnosis (53%). CK0 levels did not correlate with the severity of the psychotic symptoms. Twenty-one percent of patients had a CK0 level >1,000 IU/L. CK0 and RepCK levels were higher in males than in females (p < or = .001) and in Jewish Sephardi patients than in Ashkenazi patients (p < .007). There was no difference by diagnosis. Logarithmic (Ln) CK0 correlated with RepCK, SGOT0, LDH0, and WBC0 (r = +0.32-0.74, p < .001) but correlated inversely with serum cholesterol0 (r = -0.36, p = .002) in males. Even prominent PACK was not associated with myoglobinuria. These findings remained significant among the younger patients (aged <18 years). In males from this subgroup, LnCK0 also correlated with age (p < .007) but not with weight. In psychotic adolescents, PACK is common, is more prevalent among males, is independent of diagnosis, is influenced by ethnicity, and tends to recur.

The mediterranean fever gene modifies the progression of disability in non‐Ashkenazi Jewish multiple sclerosis patients

MS is an autoimmune, CNS demyelinating disease manifested in most patients with progressive disability. The progression rate varies between patients and may depend on modifier, immune related genes. The Mediterranean fever gene, expressed in peripheral blood leukocytes, is responsible for familial Mediterranean fever (FMF), a recessive, periodic autoinflammatory disease prevalent in Semitic populations, and less penetrant in Ashkenazi Jews. We related common, FMF associated MEFV mutations to the progression of disability in Jewish, relapsing remitting (RR) MS patients. The mutations 148Q, 694V, 695R and 726A were identified by enzymatic restriction of PCR‐amplified MEFV DNA. The progression to statuses 3 and 6 of the expanded disability status scale (EDSS) was analyzed on survival plots. 35% of 48 non‐Ashkenazi patients had one MEFV mutation. Compared to non‐carriers (n = 31) the heterozygous cohort (n = 17) represented with an increased fraction reaching both EDSS statuses (p &lt; 0.05), and with a shorter median time to reach both EDSS = 3 (2 years in carriers vs. 10 years in non‐carriers, p &lt; 0.01) and EDSS = 6 (6 vs. 23 years, respectively, p &lt; 0.005). 17% of 71 Ashkenazi patients had one MEFV mutation. There was no significant difference in the fraction of disabled or in the progression of disability between Ashkenazi carrier patients and non‐carriers. The susceptibility of the non‐Ashkenazi group attributed, in part, to the detrimental non‐Ashkenazi 694V mutation. The results suggest phenotypic expression of one mutated MEFV gene in non‐ashkenazi patients, pertinent to the pathogenesis of disability.Acknowledgements: Granted by the Israeli Ministry of Science (#6279).

Mycosis fungoides: HLA class II associations among Ashkenazi and non-Ashkenazi Jewish patients.

An immunogenetic mechanism has been suggested to play a role in the pathogenesis of mycosis fungoides (MF). While results of studies on HLA class I associations haveproved inconsistent, two previous studies showed that certain HLA class II alleles were significantly increased among North American caucasian patients with MF: HLA-DRB1*11 and DQB1*03. To investigate the possible HLA class I and class II associations with MF among Jewish patients. The patient group comprised 68 Jewish patients with MF: 38 Ashkenazi and 30 non-Ashkenazi. The control group comprised 252 healthy Jewish volunteers: 132 Ashkenazi and 120 non-Ashkenazi. Tissue typing for HLA class I (A and B) was performed using the National Institutes of Health microlymphocytotoxicity technique. DNA-based low-medium resolution analysis for DRB1* and DQB1* alleles was performed using polymerase chain reaction (PCR) amplification with sequence-specific primers. For those alleles found to have significantly increased frequency, high-resolution analysis was done by means of PCR sequence-specific oligotyping. The allele frequency of HLA-DRB1*11 was found to be significantly increased but only among Ashkenazi patients with MF (30% vs. 19% in the controls; P = 0.034). High-resolution analysis for DRB1*11, not previously performed, suggested that its greater frequency is due to the increased number of Ashkenazi MF patients with the DRB1*1104 allele (P corrected = 0.036). Analysed together, DQB1*03 alleles (DQB1*0301-0304) had a significantly greater frequency in MF as a group as compared with controls (47% vs. 33%, P = 0.003). DQB1*0301 was demonstrated to be the specific allele associated with MF in Jewish patients (allele frequency of 36% vs. 23% in controls; P corrected = 0.0068), which was not the case for North American caucasian patients with MF. No greater frequencies of any of the HLA class I A or B antigens were found. Our findings further demonstrate the 'universality' of MF HLA class II susceptibility alleles, i.e. HLA-DRB1*11 and HLA-DQB1*03, suggesting that HLA polymorphism is likely to be important in the pathogenesis of MF in Jewish patients, as it is in North American caucasian patients. Not previously reported is our finding that HLA-DRB1*1104 is the specific allele more prevalent among patients with MF. Our study also underscores some differences in HLA profiles between non-Jewish and Jewish patients with MF and between Ashkenazi and non-Ashkenazi Jewish patients, indicating the possibility of diverse HLA disease associations in populations with different genetic backgrounds. Our study provides further evidence for the lack of association between HLA class I and MF.

Mucolipidosis Type IV

Mucolipidosis type IV (MLIV) is a neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmological abnormalities, including corneal opacities, retinal degeneration, and strabismus. Severely affected as well as milder patients have been described. Over 80% of the MLIV patients are Ashkenazi Jews; the estimated heterozygote frequency in this population is 1/100. The disease is classified as a mucolipidosis due to the simultaneous lysosomal storage of lipids together with water-soluble substances. A broad spectrum of lipids and acid mucopolysaccharides were identified as the storage substances. Kinetic studies demonstrated that this heterogeneous storage stems from an abnormal endocytosis process in cells from MLIV patients of membrane components from late endosomes to the lysosomes and/or delayed efflux to the Golgi apparatus. The MLIV gene was mapped to chromosome 19p13.2–13.3 where a novel gene, MCOLN1, with MLIV-causing mutations, was identified. Two mutations were found among 95% of the Ashkenazi MLIV alleles, including an intronic acceptor splice-site mutation in 72% of the alleles and a partial gene deletion in 23%. Each of these mutations was associated with a defined haplotype in this chromosomal region. Other mutations were mostly identified in single, Ashkenazi and non-Ashkanazi patients, including missense, nonsense nucleotide deletions, and insertions. All mutations but one were identified in patients exhibiting the severe phenotype, an in-frame amino acid deletion was identified in a mild patient. MCOLN1 encodes a 580 aa protein, mucolipin 1, which is a member of a new protein family of unknown function at present, the mucolipins. Mucolipin 1 is a membrane protein with 6 transmembrane domains, a serine lipase, and nuclear localization signal motives. The protein shows homology to a group of calcium channels of the TRP/TRPL family. The involvement of this protein in the endocytosis process of membrane components is currently studied. A population screening operation among the Ashkenazi population for the detection of heterozygotes has been started in Israel as a prevention program.

The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumours in Israel.

Inherited predisposition occurs in 5–10% of all gastrointestinal (GI) cancer patients, but with the exception of colorectal cancer (CRC), the genes involved in conferring genetic susceptibility remain largely unknown. Indirect evidence indicates that germline mutations in BRCA2 might be associated with an increased risk for various GI malignancies. A single mutation (6174delT) occurs in the BRCA2 gene in high-risk breast ovarian cancer families of Jewish Ashkenazi origin, in about 1% of the general Ashkenazi population, and rarely in non-Ashkenazi Jews. In order to assess the contribution of this germline mutation to non-CRC GI cancer in Jewish Israeli patients, we tested 70 unselected, consecutive Jewish Ashkenazi patients with gastrointestinal malignancies for this mutation by PCR amplification and modified restriction enzyme digests. Patients' age range was 38–90 years (mean 65.8±11.8 years). The most common malignancies were gastric cancer (n = 35) and exocrine pancreatic cancer (n = 23). Overall, 6 mutation carriers were detected: 3/23 (13%) of the patients with pancreatic cancer, 2/35 (5.7%) of patients with gastric cancer and 1/4 (25%) of patients with bile duct cancer. The 8.6% mutation carrier rate among patients is a rate significantly higher than that of the general Ashkenazi population (1.16%P = 0.0002). We conclude that the rate of the predominant Jewish BRCA2 mutation in patients with gastric and pancreatic cancer significantly differ from that of the general population of the same ethnic origin. Thus, BRCA2 mutations probably contribute to gastrointestinal tumorigenesis other then colon cancer, and the surveillance scheme for mutation carriers should incorporate this information. © 2001 Cancer Research Campaign http://www.bjcancer.com