ankyloblepharon-ectodermal defects-cleft lip/palate syndrome At least 40 mutations in the TP63 gene have been identified in people with ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. This condition is a form of ectodermal dysplasia, which is a group of disorders characterized by abnormal development of the skin, hair, nails, teeth, and sweat glands. Other characteristic features of AEC syndrome include partial or complete fusion of the upper and lower eyelids (ankyloblepharon filiforme adnatum) and an opening in the roof of the mouth (a cleft palate), a split in the lip (a cleft lip), or both. Most of the TP63 gene mutations responsible for AEC syndrome occur in regions of the p63 protein known as the sterile alpha motif (SAM) domain and the transactivation inhibitory (TI) domain. Mutations in these regions interfere with the ability of p63 to turn target genes on and off at the right times. However, it is unclear how these changes lead to abnormal ectodermal development and the specific features of AEC syndrome. other disorders Mutations in the TP63 gene cause several additional ectodermal dysplasias with features that overlap those of AEC syndrome. These conditions include ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome; acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome; and limb-mammary syndrome (LMS). This group of disorders is characterized by varying combinations of ectodermal abnormalities (which affect the skin, hair, nails, teeth, and sweat glands), cleft lip and/or cleft palate, and malformations of the hands and feet. Mutations in the TP63 gene have also been found to cause split hand/foot malformation type 4 (SHFM4), a condition involving hand and foot malformations without any other signs or symptoms. Additionally, TP63 gene mutations are a rare cause of cleft lip and/or cleft palate that occur without features affecting other parts of the body. The TP63 gene mutations responsible for these conditions occur in various regions of the TP63 gene and affect the function of the p63 protein in different ways. Some of the known mutations may give the p63 protein a new, abnormal function (described as "gain-of-function" mutations) or lead to a version of the p63 protein that interferes with normal cell activities (described as "dominant-negative" mutations). These changes alter the ability of p63 to interact with other proteins, to turn target genes on and off at the right times, or both. It is unclear how abnormal p63 activity disrupts ectodermal development and leads to the specific features of the TP63-related conditions.

     The TP63 gene provides instructions for making a protein called tumor protein p63 (also known simply as p63). The p63 protein functions as a transcription factor, which means it attaches (binds) to certain regions of DNA and controls the activity of particular genes. The p63 protein interacts with other proteins to turn many different genes on and off at different times. The action of p63 helps regulate numerous cell activities, including cell growth and division (proliferation), cell maintenance, the process by which cells mature to carry out specific functions (differentiation), the ability of cells to stick to one another (cell adhesion), and the orderly self-destruction of cells (apoptosis). The p63 protein plays a critical role in early development. It is especially important for the normal development of ectodermal structures, such as the skin, hair, teeth, and nails. Studies suggest that it also plays essential roles in the development of the limbs, facial features, urinary system, and other organs and tissues. In addition to its roles in development, the p63 protein appears to be necessary for the maintenance of various cells and tissues later in life.

The following transcription factors affect gene expression:

• CUTL1
• p53
• Pbx1a
• MEF-2A
• Nkx2-2
• IRF-1

Tissue specificity:

Widely expressed, notably in heart, kidney, placenta, prostate, skeletal muscle, testis and thymus, although the precise isoform varies according to tissue type. Progenitor cell layers of skin, breast, eye and prostate express high levels of DeltaN-type isoforms. Isoform 10 is predominantly expressed in skin squamous cell carcinomas, but not in normal skin tissues.

Cofactor:

Binds 1 zinc ion per subunit.

Molecular Function:

• Transcription Factor Activity, Transcription Factor Binding
• Transcriptional Activator Activity, Rna Polymerase Ii Core Promoter Proximal Region Sequence-Specific Binding
• P53 Binding
• Dna Binding
• Chromatin Binding
• Damaged Dna Binding
• Double-Stranded Dna Binding
• Transcription Factor Activity, Sequence-Specific Dna Binding
• Identical Protein Binding
• Sequence-Specific Dna Binding
• Transcription Regulatory Region Dna Binding
• Metal Ion Binding
• Ww Domain Binding

Biological Processes:

• Negative Regulation Of Transcription From Rna Polymerase Ii Promoter
• Replicative Cell Aging
• Skeletal System Development
• Establishment Of Planar Polarity
• Positive Regulation Of Mesenchymal Cell Proliferation
• Epithelial Cell Development
• Chromatin Remodeling
• Apoptotic Process
• Cellular Response To Dna Damage Stimulus
• Dna Damage Response, Signal Transduction By P53 Class Mediator Resulting In Transcription Of P21 Class Mediator
• Notch Signaling Pathway
• Spermatogenesis
• Ectoderm And Mesoderm Interaction
• Proximal/Distal Pattern Formation
• Response To X-Ray
• Multicellular Organism Aging
• Response To Gamma Radiation
• Epidermal Cell Division
• Regulation Of Epidermal Cell Division
• Positive Regulation Of Keratinocyte Proliferation
• Keratinocyte Differentiation
• Embryonic Limb Morphogenesis
• Polarized Epithelial Cell Differentiation
• Hair Follicle Morphogenesis
• Mitotic G1 Dna Damage Checkpoint
• Cellular Response To Uv
• Post-Anal Tail Morphogenesis
• Odontogenesis Of Dentin-Containing Tooth
• Intrinsic Apoptotic Signaling Pathway In Response To Dna Damage By P53 Class Mediator
• Regulation Of Apoptotic Process
• Negative Regulation Of Apoptotic Process
• Regulation Of Cysteine-Type Endopeptidase Activity Involved In Apoptotic Process
• Regulation Of Neuron Apoptotic Process
• Skin Morphogenesis
• Keratinocyte Proliferation
• Negative Regulation Of Keratinocyte Differentiation
• Positive Regulation Of Osteoblast Differentiation
• Positive Regulation Of Notch Signaling Pathway
• Negative Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Sympathetic Nervous System Development
• Smooth Muscle Tissue Development
• Female Genitalia Morphogenesis
• Protein Homotetramerization
• Neuron Apoptotic Process
• Urinary Bladder Development
• Cloacal Septation
• Prostatic Bud Formation
• Squamous Basal Epithelial Stem Cell Differentiation Involved In Prostate Gland Acinus Development
• Establishment Of Skin Barrier
• Positive Regulation Of Protein Insertion Into Mitochondrial Membrane Involved In Apoptotic Signaling Pathway
• Regulation Of Signal Transduction By P53 Class Mediator
• Positive Regulation Of Cell Cycle G1/S Phase Transition
• Positive Regulation Of Fibroblast Apoptotic Process
• Negative Regulation Of Mesoderm Development
• Negative Regulation Of Cellular Senescence