title: Selective haploinsufficiency of longer isoforms of PTCH1 protein can cause nevoid basal cell carcinoma syndrome.
abstract: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. The PTCH1 gene has five alternatively used first exons resulting in the translation of three isoforms of the PTCH1 protein; that is, PTCHL, PTCHM and PTCHS. However, the biological significance of each isoform is unclear. Here we show an individual with NBCCS carrying a nonsense mutation in PTCH1 exon2, c.387G>A (p.W129X). As the mutation lay upstream of the ATG codon used for PTCHS translation, the mutant allele still expressed RNA isoforms that encode PTCHS. These results clearly demonstrate that a selective haploinsufficiency of longer isoforms of the PTCH1 protein, PTCHL and PTCHM, but not PTCHS is sufficient to cause NBCCS. Although mice selectively deficient in PTCHS isoforms are currently unavailable, this study sheds light on the complex in vivo roles of PTCH1 isoforms.
authors.affiliation: Department of Molecular Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hatsuse
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nagao
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Takayama
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Kameyama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kabasawa
authors.forename: Ken
authors.initials: K
authors.lastname: Omura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Katsunori
authors.initials: K
authors.lastname: Fujii
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyashita
mesh_terms: D001478:Basal Cell Nevus Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D018389:Codon, Nonsense / Q000235:genetics; D005091:Exons; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D018389:Codon, Nonsense; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D020033:Protein Isoforms; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins