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Biomedical subjects

A Zlotogorski

Publications and source records attributed to A Zlotogorski.

At least 19 recordsLinked to original sources
PubMed2006

TAT gene mutation analysis in three Palestinian kindreds with oculocutaneous tyrosinaemia type II; characterization of a silent exonic transversion that causes complete missplicing by exon 11 skipping.

Deficiency of the hepatic cytosolic enzyme tyrosine aminotransferase (TAT) causes marked hypertyrosinaemia leading to painful palmoplantar hyperkeratoses, pseudodendritic keratitis and variable mental retardation (oculocutaneous tyrosinaemia type II or Richner-Hanhart syndrome). Parents may therefore seek prenatal diagnosis, but this is not possible by biochemical assays as tyrosine does not accumulate in amniotic fluid and TAT is not expressed in chorionic villi or amniocytes. Molecular analysis is therefore the only possible approach for prenatal diagnosis and carrier detection. To this end, we sought TAT gene mutations in 9 tyrosinaemia II patients from three consanguineous Palestinian kindreds. In two kindreds (7 patients), the only potential abnormality identified after sequencing all 12 exons and exon-intron boundaries was homozygosity for a silent, single-nucleotide transversion c.1224G > T (p.T408T) at the last base of exon 11. This was predicted to disrupt the 5' donor splice site of exon 11 and result in missplicing. However, as TAT is expressed exclusively in liver, patient mRNA could not be obtained for splicing analysis. A minigene approach was therefore used to assess the effect of c.1224G > T on exon 11 splicing. Transfection experiments with wild-type and c.1224G > T mutant minigene constructs demonstrated that c.1224G > T results in complete exon 11 skipping, illustrating the utility of this approach for confirming a putative splicing defect when cDNA is unavailable. Homozygosity for a c.1249C > T (R417X) exon 12 nonsense mutation (previously reported in a French patient) was identified in both patients from the third kindred, enabling successful prenatal diagnosis of an unaffected fetus using chorionic villous tissue.

Adult↗
PubMed2006

Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase gene.

Multiple cutaneous and uterine leiomyomata (MCL) is an autosomal dominant disorder characterized by the development of benign smooth muscle tumours (leiomyomas) in the skin and uterus of affected women, and in the skin of affected men. In rare cases, MCL has been associated with a predisposition to the rare type II papillary renal cell cancer, also known as hereditary leiomyomatosis and renal cell cancer. The genetic locus for MCL has been mapped to chromosome 1q42.3-43 and subsequently, germline mutations in the fumarate hydratase (FH) gene have been identified. In addition, analysis of FH in some tumours of MCL patients revealed a second mutation inactivating the wild-type allele, suggesting that FH may function as a tumour suppressor gene. Here, we report two cases of MCL patients with FH mutations, designated as T287P and R190L. T287P represents a novel mutation of a highly conserved amino acid of the FH protein. In addition, a patient with an unusual clinical presentation of MCL was found to have the recurrent mutation, R190L, raising the possibility of incorporating FH sequencing as a diagnostic tool. Our findings extend the allelic series of mutations in FH and support its status as the underlying cause of MCL.

Adult↗
PubMed2005

Radiological features of central haemangioma of the jaws.

OBJECTIVES: The aim of this study was to evaluate the radiological and clinical features of central haemangioma of the jaws. METHODS: A total of 86 cases (84 from the English-language literature and two new cases) were studied and critically evaluated with emphasis on the radiological features. RESULTS: Age at time of initial diagnosis ranged from 0 to 74 years (mean 23 years, median 17 years). There was approximately equal distribution between females and males. The ratio between the mandible and maxilla was 3.3:1. Of the lesions, 69% were located in the posterior region of the jaws. Lesions were radiolucent in 96% of cases. Of the lesions, 66% were multilocular, 33% unilocular, and 1% not loculated. Borders were described in 41 cases, as well defined in 32% and diffuse in 68%. Tooth resorption was described in 23% of the lesions and tooth displacement in 16%, both more common in the mandible. The inferior alveolar nerve canal was involved in 15% of the mandibular lesions and the sinus in 35% of the maxillary lesions. CONCLUSIONS: Central haemangioma has a marked variability in its radiological appearance and should be considered in the differential diagnosis of many unilocular or multilocular radiolucent lesions of the jaws, especially in the mandible. Some radiographic patterns, such as the spoke-like and sunray appearance frequently described in the literature, are actually extremely rare.

Adolescent↗
PubMed2003

Recurrent missense mutations in the hair keratin gene hHb6 in monilethrix.

Monilethrix is an autosomal dominant hair disorder characterized by a beaded appearance of the hair resulting from periodic thinning of the shaft (MIM 158000). The phenotype shows variable penetrance and results in hair fragility and patchy dystrophic alopecia. Mutations of the helix-encoded region in two hair-specific keratins (hHb1 and hHb6) have been identified as responsible for this disorder. We investigated two unrelated families from Russia and Colombia with monilethrix and found two missense mutations in hHb6. In the Russian family, we found a G to A transition at the first base of codon 402, resulting in a lysine substitution (GAG to AAG), designated E402K. In the Colombian family, affected patients carried a missense mutation of codon 413, involving a transition from G to A causing a lysine substitution (GAG to AAG), designated E413K. These two mutations have been identified in other monilethrix families from Europe. Our findings extend the body of evidence implicating recurrent hHb6 and hHb1 mutations in monilethrix families from around the world.

Colombia↗
PubMed2003

Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24.

BACKGROUND: The identification of the molecular basis of disorders of keratinisation has significantly advanced our understanding of skin biology, revealing new information on key structures in the skin, such as the intermediate filaments, desmosomes, and gap junctions. Among these disorders, there is an extraordinarily heterogeneous group known as palmoplantar keratodermas (PPK), for which only a few molecular defects have been described. A particular form of PPK, known as punctate PPK, has been described in a few large autosomal dominant pedigrees, but its genetic basis has yet to be identified. AIM: Identification of the gene for punctate PPK. METHODS: Clinical examination and linkage analysis in three families with punctate PPK. RESULTS: A genomewide scan was performed on an extended autosomal dominant pedigree, and linkage to chromosome 15q22-q24 was identified. With the addition of two new families with the same phenotype, we confirmed the mapping of the locus for punctate PPK to a 9.98 cM interval, flanked by markers D15S534 and D15S818 (maximum two point lod score of 4.93 at theta = 0 for marker D15S988). CONCLUSIONS: We report the clinical and genetic findings in three pedigrees with the punctate form of PPK. We have mapped a genetic locus for this phenotype to chromosome 15q22-q24, which indicates the identification of a new gene involved in skin integrity.

Chromosome Mapping↗
PubMed2001

Clinical and molecular diagnostic criteria of congenital atrichia with papular lesions.

Congenital atrichia with papular lesions is a rare, autosomal recessive form of total alopecia and mutations in the hairless (hir) gene have been implicated in this disorder. Published estimates of the prevalence of this disorder remain surprisingly low considering pathogenetic mutations in hir have been found in distinct ethnicities around the world. Therefore, it is likely that congenital atrichia with papular lesions is far more common than previously thought and is often mistaken for its phenocopy, the putative autoimmune form of alopecia universalis. To clarify this discrepancy, we propose criteria for the clinical diagnosis of congenital atrichia with papular lesions. Among these is the novel report of the consistent observation of hypopigmented whitish streaks on the scalp surface of affected individuals. Additionally, we report the identification of a novel missense mutation in hir from a family of Arab Palestinian origin that exhibits the pathognomonic features of atrichia with papular lesions. Collectively, we anticipate that an increased recognition of this disorder will result in more accurate diagnosis and the sparing of unnecessarily treatment to patients.

Alopecia↗
PubMed2000

Two p16 (CDKN2A) germline mutations in 30 Israeli melanoma families.

Germline mutations in the p16 (CDKN2A) tumour suppressor gene have been linked to inherited predisposition to malignant melanoma (MM). Variable frequencies of p16 germline mutations were reported in different collections of melanoma families but it can be as high as 50%. Here we describe the results of p16 mutation screening in 30 melanoma kindreds in Israel. The entire coding region of the p16 gene, including exons 1, 2 and 3, flanking exon/intron junctions, and a portion of the 3' untranslated (UTR) region of the gene were examined by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing. Two p16 germline mutations were identified: G101W, which has been previously observed in a number of melanoma kindreds, and G122V, a novel missense mutation. Thus, the frequency of mutations identified in this collection of Israeli families was 7%. Functional analysis indicated that the novel G122V variant retained some capacity to interact with cyclin dependent kinases (CDKs) in vitro, yet it was significantly impaired in its ability to cause a G1 cell cycle arrest in human diploid fibroblasts. This partial loss of function is consistent with the predicted impact of G122V substitution on the 3-dimensional structure of the p16 protein.

Adolescent↗
PubMed2000

Haim-Munk syndrome and Papillon-Lefèvre syndrome are allelic mutations in cathepsin C.

Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction. Although both PLS and HMS share the cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS including arachnodactyly, acro-osteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers. While PLS cases have been identified throughout the world, HMS has only been described among descendants of a religious isolate originally from Cochin, India. Parental consanguinity is a characteristic of many cases of both conditions. Although autosomal recessive transmission of PLS is evident, a more "complex" autosomal recessive pattern of inheritance with phenotypic influences from a closely linked modifying locus has been hypothesised for HMS. Recently, mutations of the cathepsin C gene have been identified as the underlying genetic defect in PLS. To determine if a cathepsin C mutation is also responsible for HMS, we sequenced the gene in affected and unaffected subjects from the Cochin isolate in which both the PLS and HMS phenotypes appear. Here we report identification of a mutation of cathepsin C (exon 6, 2127A--> G) that changes a highly conserved amino acid in the cathepsin C peptide. This mutation segregates with HMS in four nuclear families. Additionally, the existence of a shared common haplotype for genetic loci flanking the cathepsin C gene suggests that affected subjects descended from the Cochin isolate are homozygous for a mutation inherited "identical by descent" from a common ancestor. This finding supports simple autosomal recessive inheritance for HMS in these families. We also report a mutation of the same exon 6 CTSC codon (2126C-->T) in a Turkish family with classical PLS. These findings provide evidence that PLS and HMS are allelic variants of cathepsin C gene mutations.

Alleles↗
PubMed1999

Genomic organization of the human hairless gene (HR) and identification of a mutation underlying congenital atrichia in an Arab Palestinian family.

Congenital atrichia is a rare form of hereditary human hair loss, characterized by the complete shedding of hair shortly after birth, together with the formation of papular lesions on the skin. Recently, we cloned the human homolog of the mouse hairless gene and identified pathogenic mutations in several families with inherited congenital atrichia. Here, we present the genomic organization of the human hairless gene (HGMW-approved symbol HR), which spans over 14 kb on chromosome 8p12 and is organized into 19 exons. In addition, we report the identification of a 22-bp deletion mutation in exon 3 of the hairless gene in a large consanguineous Arab Palestinian family from a village near Jerusalem, Israel. These findings extend the body of evidence implicating mutations in the hairless gene as an underlying cause of congenital atrichia in humans.

Alopecia↗
PubMed1999

Bullous erysipelas: A retrospective study of 26 patients.

BACKGROUND: Erysipelas is a superficial form of cellulitis caused by a variety of microbes, and it responds to antibiotic treatment. During the past few years we treated several patients with a bullous form of erysipelas involving the lower legs. We believe their disease had a more protracted course than patients with nonbullous erysipelas. OBJECTIVE: We studied bullous erysipelas by conducting a retrospective analysis of 26 patients with bullous erysipelas of the legs treated by the authors during a 5-year period. METHODS: We conducted a retrospective review of the records of all patients with a diagnosis of bullous erysipelas who were treated at the Department of Dermatology, Hadassah Medical Center, Jerusalem, between the years 1992 and 1996. Data regarding patients with nonbullous erysipelas were obtained from the medical center's computerized data pool. RESULTS: A total of 26 cases of bullous erysipelas were found, comprising 22 women and 4 men whose ages ranged from 28 to 87 (mean, 58.8) years. The average hospital stay was 20.57 days (range, 12 to 46 days). The average hospital stay for patients with nonbullous erysipelas and cellulitis treated in the same department by the authors during the study period was 10.6 days (range, 2 to 54 days). CONCLUSION: Bulla formation is a complication of erysipelas, seen in our series in 5.2% of the patients (26 of 498 admissions for erysipelas and cellulitis). The course of the disease is protracted, requiring longer medical attention.

Adult↗
PubMed1999

Gastric-Mucocutaneous gammadelta T cell lymphoma: possible association with Epstein-Barr virus?

Gammadelta T cell lymphoma is usually either subcutaneous or hepato-splenic and involvement of other extranodal sites is rare. Here we report an unusual case of gammadelta T cell lymphoma involving the subcutaneous tissue, vocal cords, gastric mucosa and the central nervous system with a rapidly progressive clinical course and fatal outcome. Epstein-Barr virus (EBV) was shown to be present in the tumor cells, and is thought to play a role in the pathophysiology of this particular case of lymphoma.

Adult↗
PubMed1998

Congenital atrichia in five Arab Palestinian families resulting from a deletion mutation in the human hairless gene.

Congenital atrichia is a rare autosomal recessive disorder of hair development, characterized by complete loss of hair shortly after birth. Evidence of linkage to chromosome 8p12 has been established, implicating the human homolog of the mouse hairless (hr) gene as a candidate gene. We have previously identified missense mutations in families with congenital atrichia. Here, we report the first deletion mutation (2147del C) in exon 9 of the human hairless gene leading to a frameshift and downstream premature termination codon in five Palestinian families of Arab origin.

Alopecia↗
PubMed1998

Cutaneous lymphoma in Israel, 1985-1993: a population-based incidence study.

The incidence rate of cutaneous lymphomas (CL) [including mycosis fungoides (MF) and non-mycosis fungoides (non-MF)] for the period 1985-93 in Israel was determined using data from the population-based Cancer Registry supplemented by a field survey that covered approximately 80% of lymphoma cases. After the field survey, corrected rates were 49% and 24% higher for MF and non-MF respectively (37% for CL overall). The age-adjusted incidence rates per 100,000 were 1.18 and 0.63 for Jewish men and women respectively. MF rates (0.77 in men and 0.35 in women) were higher than non-MF (0.41 and 0.28 respectively). Rates of CL were significantly lower in non-Jews. There were no significant differences in incidence among Jewish ethnic subgroups. However, the lack of variability in the incidence of these neoplasms among subpopulations is in contrast with findings for cutaneous malignant melanoma; the observed high rates of CL could, nonetheless, be consistent with the sunlight exposure hypothesis, operating perhaps through a different mechanism.

Cohort Studies↗
PubMed1998

Monilethrix: a keratin hHb6 mutation is co-dominant with variable expression.

Monilethrix is a rare autosomal dominant disease characterized by hair fragility and hyperkeratotic papules. Mutations in type-II hair specific keratins hHb6 and hHb1 have recently been reported. We describe a large family with a E410D mutation in the evolutionary conserved helix termination motif of keratin hHb6 that was variably expressed among 12 heterozygous members, and severely expressed among 3 homozygous members. These 3 patients had essentially complete lack of scalp hair since the age of 2 months with no improvement over time as well as follicular keratotic involvement extensively expressed over the scalp and large body areas. The variability seen in heterozygous patients, along with seasonal and pregnancy-related improvement suggest that other genetic or environmental factors may modify keratin gene expression. This represents the first report of a co-dominant keratin hHb6 mutation resulting in severe disease.

Base Sequence↗