Doron M. Behar

Mutations in GALNT3 , encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis

Familial tumoral calcinosis (FTC; OMIM 211900) is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Using linkage analysis, we mapped the gene underlying FTC to 2q24–q31. This region includes the gene GALNT3, which encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation. Sequence analysis of GALNT3 identified biallelic deleterious mutations in all individuals with FTC, suggesting that defective post-translational modification underlies the disease.

Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders.

AbstractHyperphosphatemia-hyperostosis syndrome (HHS) is a rare autosomal recessive metabolic disorder characterized by elevated serum phosphate levels and repeated attacks of acute, painful swellings of the long bones with radiological evidence of periosteal reaction and cortical hyperostosis. HHS shares several clinical and metabolic features with hyperphosphatemic familial tumoral calcinosis (HFTC), which is caused by mutations in GALNT3 encoding a glycosyltransferase responsible for initiating O-glycosylation. To determine whether GALNT3 is involved in the pathogenesis of HHS we screened two unrelated Arab-Israeli HHS families for pathogenic mutations in this gene. All affected individuals harbored a homozygous splice site mutation (1524+1G↧A) innGALNT3. This mutation was previously described in a large Druze HFTC kindred and has been shown to alter GALNT3nexpression and result in ppGalNAc-T3 deficiency. Genotype analysis of six microsatellite markers across the GALNT3nregion on 2q24-q31 revealed that the HHS and HFTC families share a common haplotype spanning approximately 0.14xa0Mb. Our results demonstrate that HHS and HFTC are allelic disorders despite their phenotypic differences and suggest a common origin of the 1524+1G↧A mutation in the Middle East (founder effect). The heterogeneous phenotypic expression of the identified splice site mutation implies the existence of inherited or epigenetic modifying factors of importance in the regulation of ppGalNAc-T3 activity.

Contrasting patterns of Y chromosome variation in Ashkenazi Jewish and host non-Jewish European populations

The molecular basis of more than 25 genetic diseases has been described in Ashkenazi Jewish populations. Most of these diseases are characterized by one or two major founder mutations that are present in the Ashkenazi population at elevated frequencies. One explanation for this preponderance of recessive diseases is accentuated genetic drift resulting from a series of dispersals to and within Europe, endogamy, and/or recent rapid population growth. However, a clear picture of the manner in which neutral genetic variation has been affected by such a demographic history has not yet emerged. We have examined a set of 32 binary markers (single nucleotide polymorphisms; SNPs) and 10 microsatellites on the non-recombining portion of the Yxa0chromosome (NRY) to investigate the ways in which patterns of variation differ between Ashkenazi Jewish and their non-Jewish host populations in Europe. This set of SNPs defines a total of 20 NRY haplogroups in these populations, at least four of which are likely to have been part of the ancestral Ashkenazi gene pool in the Near East, and at least three of which may have introgressed to some degree into Ashkenazi populations after their dispersal to Europe. It is striking that whereas Ashkenazi populations are genetically more diverse at both the SNP and STR level compared with their European non-Jewish counterparts, they have greatly reduced within-haplogroup STR variability, especially in those founder haplogroups that migrated from the Near East. This contrasting pattern of diversity in Ashkenazi populations is evidence for a reduction in male effective population size, possibly resulting from a series of founder events and high rates of endogamy within Europe. This reduced effective population size may explain the high incidence of founder disease mutations despite overall high levels of NRY diversity.

Diagnosis and Treatment of Urinary Tract Complication in Crohn’s Disease: An Experience over 15 Years

BACKGROUD: Urinary tract complications in Crohn’s disease are common but treatable, and often present diagnostic and therapeutic dilemmas.

Long-term prognosis of acute pulmonary oedema — an ominous outcome

Acute pulmonary oedema (APOE) is a major health problem, leading to poor hospital and long‐term outcomes. There is a relative paucity of studies describing prognosis of consecutive unsolicited patients diagnosed with APOE and hospitalized in internal medicine departments.

Prospective evaluation of pulmonary edema.

Objectives: To describe the clinical profile and hospital outcome of successive unselected patients with pulmonary edema hospitalized in an internal medicine department. Design: Prospective, consecutive, unsolicited patients diagnosed with pulmonary edema. Setting: An internal medicine department in a 900 tertiary care center. Patients: A total of 150 consecutive unselected patients (90 males, 60 females; median age, 75 yrs). Results: Ischemic heart disease, hypertension, various valvular lesions and diabetes mellitus were present in 85%, 70%, 53%, and 52% of patients, respectively. Acute myocardial infarction at admission was observed in 15% of patients. The most common precipitating factors associated with the development of pulmonary edema included: high blood pressure (29%), rapid atrial fibrillation (29%,) unstable angina pectoris (25%), infection (18%), and acute myocardial infarction (15%). Twenty‐two patients (15%) were mechanically ventilated. Eighteen patients (12%) died while in the hospital, and the cause of death was cardiac pump failure in 82%. The median hospital stay was 10 days. Predictors for increase rate of in‐hospital mortality included: diabetes (p < .05), orthopnea (p < .05), echocardiographic finding of moderate‐to‐severely depressed global left ventricular systolic function (p < .001), acute myocardial infarction during hospital stay (p < .001), hypotension/shock (p < .05), and the need for mechanical ventilation (p < .001). Conclusions: Most patients with pulmonary edema in the internal medicine department are elderly, having ischemic heart disease, hypertension, diabetes, and a previous history of pulmonary edema. The overall mortality is high (in‐hospital, 12%) and the predictors associated with high in‐hospital mortality are related to left ventricular myocardial function. The long median hospital stay (10 days) and the need for many cardiovascular drugs, impose a considerable cost in the management and health care of these patients.

Erratum to: Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5

Lissencephaly comprises a heterogeneous group of developmental brain disorders of varying severity, involving abnormal cortical gyration. We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Using microarray-based homozygosity mapping in the reported family, combined with whole exome sequencing in one affected infant, we identified a homozygous splice site mutation g.IVS8+1G>A in cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162SfsX19). The mutation co-segregated with the disease phenotype in all 29 study participants (4 patients and 25 healthy relatives), and was not identified in 200 ethnically matched control chromosomes. The p.V162SfsX19 mutation causes lack of endogenous CDK5 expression in affected dermal fibroblasts and brain tissue at the mRNA and protein levels, consistent with nonsense-mediated mRNA decay. Functional analysis of the p.V162SfsX19 mutation, using a yeast complementation assay, showed loss-of-function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family.

Left Hydronephrosis Caused by Crohn Disease Successfully Treated Conservatively

We report the case of a 35-year-old man who presented with fever, diarrhea, and a left abdominal mass. Diagnostic studies confirmed Crohn disease and revealed an abdominal mass obstructing the left ureter with hydroureter and hydronephrosis. The patient was successfully treated conservatively, with corticosteroids and mesalamine, A review of the literature indicates a predominance of right ureteral involvement in Crohn disease, associated with a high incidence of ileocecal disease. Most of these patients were treated surgically, with resection of ileocecal lesion and/or ureterolysis. Ureteral obstruction as a complication of Crohn disease is discussed, with emphasis on conservative treatment.

Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening

Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan‐population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients.