PTCH mutations: distribution and analyses

Abstract

Mutations in the PTCH (PTCH1) gene are the underlying cause of nevoid basal cell carcinoma syndrome (NBCCS), and are also found in many different sporadic tumors in which PTCH is thought to act as a tumor suppressor gene. To investigate the distribution pattern of these mutations in tumors and NBCCS, we analyzed 284 mutations and 48 SNPs located in the PTCH gene that were compiled from our PTCH mutation database. We found that the PTCH mutations were mainly clustered into the predicted two large extracellular loops and the large intracellular loop. The SNPs appeared to be clustered around the sterol sensing domain and the second half of the protein. The NBCCS cases and each class of tumor analyzed revealed a different distribution of the mutations in the various PTCH domains. Moreover, the types of mutations were also unique for the different groups. Finally, the PTCH gene harbors mutational hot spot residues and regions, including a slippage-sensitive sequence in the N-terminus.

Germline PTCH1 mutations in Japanese basal cell nevus syndrome patients

“…The PTCH1 mutations reported so far in BCNS are scattered over the entire gene without any apparent hot spots. 11 All available PTCH1 molecular data of the Japanese BCNS patients also indicated a dispersed distribution of mutations in all regions and suggested no founder effect (Table 3). 16,[18][19][20][21][22][23][24][25][26] The typical symptoms of the Japanese BCNS patients are characterized by palmar and plantar pits, odontogenic keratocysts and abnormal skeletons and are sometimes accompanied by BCC, especially in elderly patients.…”

“…10 Hh signaling activation due to impaired PTCH1 function was reported in BCNS and also among malignant neoplasms, such as sporadic BCC, medulloblastoma/primitive neuroectodermal tumor, breast cancer, colon cancer and meningioma. 11 Human PTCH1, a homolog of the Drosophila segment polarity gene patched (ptc), has at least 23 exons spanning B50 kb and is located on chromosome 9q22.32. It encodes an integral membrane protein of 1447 amino acids.…”

“…To date, B300 mutations, including nonsense and missense mutations, insertions, deletions and splicing mutations, have been identified in the PTCH1 gene. 11 Half of the mutations were reported in BCNS cases and the rest were in sporadic tumors, including BCC and medulloblastoma. However, the majority of the data were obtained from Caucasian BCNS patients.…”

Sonic hedgehog signaling in kidney fibrosis: a master communicator

“…In the absence of ligand binding, Ptch2 has a decreased ability to inhibit the activity of Smo, compared with Ptch1 (Alfaro et al, 2014; Zhulyn et al, 2015). Structurally, Ptch protein has a sterol sensing domain (SSD), which is essential for inhibiting the activity of Smo (Lindstrom et al, 2006). Normally, Ptch acts as a sterol pump and removes oxysterols produced by 7-dehydrocholesterol reductase.…”

Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression

“…Germline missense mutations (17%) occur primarily in the transmembrane domains and especially in the SSDs. (16) Loss of heterozygosity of the PTCH1 gene (>17%) is a common event in patients that are PTCH1 point mutation-negative. In addition, patients harboring PTCH1 deletions of less than 2.4 Mb in size do not exhibit phenotypes atypical for NBCCS.…”