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59


A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome

Hu, Guofang; Onder, Meltem; Gill, Melissa; Aksakal, Burhan; Oztas, Murat; Gürer, M Ali; Celebi, Jülide Tok
Brooke-Spiegler syndrome (BSS, familial cylindromatosis or turban tumor syndrome) is an inherited disease characterized by neoplasms of the skin appendages such as cylindroma, trichoepithelioma, and spiradenoma. The disease has been mapped to 16q12-13, and mutations in the CYLD gene have been identified in families with this disorder. Of interest, multiple familial trichoepithelioma (MFT) has been described as a distinct disorder characterized by the familial occurrence of trichoepitheliomas. MFT has been mapped to 9p21; however, to date a candidate gene has not been identified. In this report, we describe a four-generation family with BSS presenting predominantly with trichoepitheliomas (resembling MFT phenotype). We identified a novel missense mutation in the CYLD gene, designated E474G, in the affected individuals of this family. Our findings exemplify clinical heterogeneity within BSS and extend the body of evidence that mutations in CYLD are implicated in this disease. Although not conclusive, these findings suggest that BSS and MFT may represent a single entity.
PMID: 14632188
ISSN: 0022-202x
CID: 5181142

Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome [Case Report]

Scheinfeld, N; Hu, G; Gill, M; Austin, C; Celebi, J T
Brooke-Spiegler syndrome is an autosomal dominantly inherited disease with predisposition to neoplasms of the skin appendages. The disease has been mapped to 16q, and mutations in the CYLD gene have been identified in families with this disorder. We describe an individual with BSS exhibiting clinical heterogeneity in which a heterozygous frameshift mutation in CYLD, 2172delA, has been identified. These findings extend the body of evidence that mutations in CYLD are involved in Brooke-Spiegler syndrome and provide additional information for phenotype-genotype correlation.
PMID: 12950348
ISSN: 0307-6938
CID: 5181122

A novel mutation in the ARS (component B) gene encoding SLURP-1 in a family with Mal de Meleda [Case Report]

Yerebakan, O; Hu, G; Yilmaz, E; Celebi, J T
Mal de Meleda is a rare, autosomal recessive form of palmoplantar keratoderma. The disease has been mapped to chromosome 8 qter, and recently mutations in the ARS (component B) gene have been identified in families with this disorder. We describe a small family of Turkish origin with Mal de Meleda and identified a novel homozygous mutation, L98P, in ARS (component B). These findings extend the body of evidence implicating mutations in the ARS (component B) gene in Mal de Meleda.
PMID: 12950349
ISSN: 0307-6938
CID: 5181132

Identification of a recurrent mutation in keratin 6a in a patient with overlapping clinical features of pachyonychia congenita types 1 and 2 [Case Report]

Ward, K M; Cook-Bolden, F E; Christiano, A M; Celebi, J T
Pachyonychia congenita is characterized by hypertrophic nail dystrophy and associated ectodermal features. PC-1 subtype is associated with mutations in keratins 6a or 16, whereas PC-2 subtype is linked to mutations in keratins 6b or 17. The correlation between the mutated gene and the type of PC has generally been consistent. In this report, we describe a case with overlapping clinical features of PC-1 and PC-2 in which a mutation in K6a was identified.
PMID: 12823309
ISSN: 0307-6938
CID: 5181102

Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability

McCarthy, Ellen E; Celebi, Julide T; Baer, Richard; Ludwig, Thomas
The BRCA1 tumor suppressor has been implicated in many cellular pathways, but the mechanisms by which it suppresses tumor formation are not fully understood. In vivo BRCA1 forms a heterodimeric complex with the related BARD1 protein, and its enzymatic activity as a ubiquitin ligase is largely dependent upon its interaction with BARD1. To explore the genetic relationship between BRCA1 and BARD1, we have examined the phenotype of Bard1-null mice. These mice become developmentally retarded and die between embryonic day 7.5 (E7.5) and E8.5. Embryonic lethality results from a severe impairment of cell proliferation that is not accompanied by increased apoptosis. In the absence of p53, the developmental defects associated with Bard1 deficiency are partly ameliorated, and the lethality of Bard1; p53-nullizygous mice is delayed until E9.5. This result, together with the increased chromosomal aneuploidy of Bard1 mutant cells, indicates a role for Bard1 in maintaining genomic stability. The striking similarities between the phenotypes of Bard1-null, Brca1-null, and double Bard1; Brca1-null mice provide strong genetic evidence that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer.
PMCID:162231
PMID: 12832489
ISSN: 0270-7306
CID: 5181112

A recurrent mutation in the ARS (component B) gene encoding SLURP-1 in Turkish families with mal de Meleda: evidence of a founder effect

Hu, Guofang; Yildirim, Mehmet; Baysal, Vahide; Yerebakan, Ozlem; Yilmaz, Ertan; Inaloz, H Serhat; Martinez-Mir, Amalia; Christiano, Angela M; Celebi, Julide Tok
Mal de Meleda is a rare form of palmoplantar keratoderma, and recently mutations in the ARS (component) B gene have been identified in families with this disease. We identified a recurrent nonsense mutation, R96X, in four families of Turkish descent. In this report, we demonstrate that these families share a common ancestral haplotype at the mal de Meleda locus, suggesting a founder effect.
PMID: 12787122
ISSN: 0022-202x
CID: 5181092

Identification of recurrent mutations in the ARS (component B) gene encoding SLURP-1 in two families with mal de Meleda

Ward, Kimberley Morine; Yerebakan, Ozlem; Yilmaz, Ertan; Celebi, Jülide Tok
Mal de Meleda is a rare, autosomal recessive form of palmoplantar keratoderma. The disease has been mapped to chromosome 8qter, and in a recent study mutations in the ARS gene have been identified in families with this disorder. Here, we report two unrelated families with mal de Meleda, in which two different homozygous mutations in the ARS gene were identified. These findings support the notion that mutations in the ARS gene are pathogenic in mal de Meleda.
PMID: 12535203
ISSN: 0022-202x
CID: 5181082

Acute infectious purpura fulminans associated with asplenism or hyposplenism [Case Report]

Ward, Kimberley Morine; Celebi, Julide Tok; Gmyrek, Robyn; Grossman, Marc E
Acute infectious purpura fulminans is a rapidly progressive syndrome of hemorrhagic skin necrosis associated with acute infection and disseminated intravascular coagulation. We report 5 cases of purpura fulminans and briefly review the literature. All cases were associated with encapsulated organisms (Streptococcus pneumoniae or Group A streptococcus), and 4 of the 5 patients had asplenism or functional hyposplenism.
PMID: 12271289
ISSN: 0190-9622
CID: 5181072

Identification of a PTEN mutation in a family with Cowden syndrome and Bannayan-Zonana syndrome

Wanner, M; Celebi, J T; Peacocke, M
Cowden syndrome (CS) and Bannayan-Zonana syndrome (BZS) are two inherited hamartoma syndromes characterized by distinct phenotypic features. Mutations in the PTEN gene have been identified in patients with CS and BZS, suggesting the presence of a common genetic basis. We describe a single kindred with individuals manifesting both CS and BZS phenotypes (CS/BZS overlap family) in which we have identified a novel mutation in PTEN by DNA sequencing. We have confirmed these results by means of restriction enzyme analysis. The presence of individuals with CS and BZS within the same family, and moreover the identification of identical PTEN gene mutations in these individuals, suggest that these two syndromes represent different phenotypic expressions of one disease. Furthermore, these findings imply that, like patients with CS, individuals with BZS should be monitored for the onset of malignancy.
PMID: 11174374
ISSN: 0190-9622
CID: 5181062

Association of splicing defects in PTEN leading to exon skipping or partial intron retention in Cowden syndrome [Case Report]

Celebi, J T; Wanner, M; Ping, X L; Zhang, H; Peacocke, M
Cowden syndrome (CS) and Bannayan Zonana syndrome (BZS) are two autosomal dominantly inherited conditions characterized by hamartomas. Mutations in PTEN, a tumor suppressor gene located on chromosome 10q23, have been identified in patients with phenotypic findings of both CS and BZS. These mutations are found throughout the entire gene, with exon 5 being the most common site, and include point mutations, insertions and deletions. To date, 11 point mutations at the splice junctions of the PTEN gene have been reported, however, data on the alterations in the transcripts have been lacking. In this study, we have identified three novel splice site mutations in PTEN, in two families with CS and in one individual with BZS. One mutation affected the splice-acceptor site, which resulted in out-of-frame skipping of an entire exon. By contrast, the other two mutations affected the splice-donor sites, and both showed inclusion of partial intronic sequences in the transcript due to activation of cryptic splice sites. These data demonstrate mRNA alterations as a consequence of splice site mutations in the PTEN gene.
PMID: 11071384
ISSN: 0340-6717
CID: 5181052