Genomes and Genes
CONNEXINS AND THEIR ROLE IN EPIDERMAL DIFFERENTIATION
Principal Investigator: G Richard
Abstract: The proposed project is designed to provide me with the knowledge practical tools and experience in cellular biology to establish a strong, independent research program integrating dermatology, molecular genetics and cutaneous biology to study inherited skin disorders. The Department of Dermatology and Cutaneous Biology at Jefferson Medical College has an outstanding research program, and will provide laboratory facilities, equipment, resources and time to support this proposal. The research aims to identify the spectrum of connexin defects involved in inherited skin disorders. The Department of Dermatology and Cutaneous Biology at Jefferson Medical College has an outstanding successful research program, and will provide laboratory facilities, equipment, resources and time to support this proposal. The research aims to identify the spectrum of connexin defects involved in human inherited skin disorders, and to elucidate the role of connexins and gap junctional intercellular communication in normal and diseased skin. It is based on my extensive clinical linkage and molecular genetic studies of erythrokeratodermia variabilis (EKV) that recently resulted in the cloning of two novel human connexin genes, GJB3 and GJB5, and the disclosure of mutations in GJB3 as proximal cause of EKV. Moreover, I identified pathogenic mutations in GJB3 as proximal cause of EKV. Moreover, I identified pathogenic mutations in another connexin gene (GJB2) in a family with dominant palmoplantar keratoderma associated with deafness, and demonstrated in a collaborative study evidence for a dominant inhibitory effect of the mutant protein Cx26 on gap junction function. I now plan to clone the human GJB4 gene, and to screen the epidermally expressed connexin genes for mutations in EKV, other erythrokeratodermias and disorders of cornification, which will allow to define the spectrum of genodermatoses caused by connexin defects. In addition, the project focuses on the comprehensive characterization of the complex gap junction network of human skin, which might be formed by as many as 8 connexins, and its function in normal and disturbed epidermal differentiation. The development of antibodies against human Cx31 and rat Cx30.3 will facilitate immunohistochemical studies to evaluate the spatial and differential expression of all epidermal connexins. We will test the hypothesis that connexin mutations have a dominant- inhibitory effect on normal channel function, which is crucial for normal epidermal differentiation, with functional studies in different expression system. Constructs of normal and mutant connexin genes will e expressed in paired Xenopus oocytes, and their ability to form functional intercellular channel is measured by voltage clamp. Stable transfected HeLa cells will be used to study the intracellular sub-localization of different mutant Cx, while gap junctional intercellular communication is evaluated using the dye transfer technique. We expect that these approaches provide critical information on the patho-mechanism of connexin defects in skin.
Funding Period: 2000-03-06 - 2005-02-28
more information: NIH RePORT
- Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disordersYaacov Frishberg
Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel
J Mol Med (Berl) 83:33-8. 2005..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...
- Malignant proliferating pilar tumors arising in KID syndrome: a report of two patientsGurston G Nyquist
Department of Otolaryngology, Head and Neck Surgery, Kaiser Permanente, Oakland, CA, USA
Am J Med Genet A 143:734-41. 2007..Based on our findings, we believe that cancer surveillance in patients with KID syndrome should include screening for pilar tumors and their early removal to avoid development of malignant proliferating pilar tumors with poor prognosis...
- Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14Jennie Lugassy
Department of Dermatology and Laboratory of Molecular Dermatology, Rambam Health Care Campus, Technion Israel Institute of Technology, Haifa, Israel
Am J Hum Genet 79:724-30. 2006....
- A novel GJA 1 mutation in oculo-dento-digital dysplasia with curly hair and hyperkeratosisSusan C Kelly
Department of Dermatology, Lehigh Valley Hospital, Allentown, Pennsylvania, USA
Eur J Dermatol 16:241-5. 2006..In the light of the cutaneous findings in our patient and based on recent ectodermal dysplasia classification systems, we propose to include ODDD in the group of ectodermal dysplasias...
- Epidermolysis Bullosa Simplex with mottled pigmentation: mutation analysis in the first reported Hispanic pedigree with the largest single generation of affected individuals to dateDaniel Shurman
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA, and Department of Clinical Genetics, Helsinki University Central Hospital, Finland
Eur J Dermatol 16:132-5. 2006..In both families, the heterozygous transition mutation 74C-->T of the keratin 5 gene, which results in amino acid substitution P25L, completely co-segregated with the EBS-MP phenotype...
- Properties of human connexin 31, which is implicated in hereditary dermatological disease and deafnessCharles K Abrams
Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
Proc Natl Acad Sci U S A 103:5213-8. 2006..These findings provide an important first step in evaluating the pathogenesis of inherited human diseases associated with mutations in the gene for Cx31...
- Netherton syndrome with extensive skin peeling and failure to thrive due to a homozygous frameshift mutation in SPINK5Adam S Geyer
Department of Dermatology, Columbia University Medical Center, Columbia University, New York, NY, USA
Dermatology 210:308-14. 2005..The disorder is caused by deleterious mutations in the SPINK5 gene, encoding the serine protease inhibitor LEKTI...
- In vivo and in vitro expression of connexins in the human corneal epitheliumDaniel L Shurman
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Invest Ophthalmol Vis Sci 46:1957-65. 2005..It also evaluates the pathologic effects of a pathogenic missense mutation in Cx26, which causes keratitis-ichthyosis-deafness syndrome (KIDS), a rare genetic disorder with corneal involvement...
- Bigenic connexin mutations in a patient with hidrotic ectodermal dysplasiaRichard Kellermayer
Department of Medical Genetics and Child Development, University Medical School of Pecs, József A u 7, Pecs 7623, Hungary
Eur J Dermatol 15:75-9. 2005..Our findings suggest that GJA1 mutations can produce variable clinical phenotypes on the background of sequence variants in other connexins...
- Connexin disorders of the skinGabriele Richard
Department of Dermatology and Cutaneous Biology and the Jefferson Institute of Molecular Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA
Clin Dermatol 23:23-32. 2005..This review aims to delineate the cutaneous connexin disorders and to highlight intriguing genotype-phenotype correlations and emanating clinical implications...
- LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosumAkemi Ishida-Yamamoto
Department of Dermatology, Asahikawa Medical College, Midorigaoka Higashi 2 1 1 1, Asahikawa 078 8510, Japan
J Invest Dermatol 124:360-6. 2005..Our data provide new insights into the biological functions of LG and the pathogenesis of NS...
- KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndromeJennie Lugassy
Laboratory of Molecular Dermatology and Department of Dermatology, Rambam Health Care Campus, Haifa, Israel
J Invest Dermatol 128:1517-24. 2008....