title: Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer.
abstract: Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles. To date, two different loci in chromosomal regions 15q22-15q24 and 8q24.13-8q24.21 have been reported. Pathogenic mutations, however, have yet to be identified. In order to elucidate the genetic cause of PPKP type Buschke-Fischer-Brauer (PPKP1), we performed exome sequencing in five affected individuals from three families, and we identified in chromosomal region 15q22.33-q23 two heterozygous nonsense mutations-c.370C>T (p.Arg124(∗)) and c.481C>T (p.Arg161(∗))-in AAGAB in all affected individuals. Using immunoblot analysis, we showed that both mutations result in premature termination of translation and truncated protein products. Analyses of mRNA of affected individuals revealed that the disease allele is either not detectable or only detectable at low levels. To assess the consequences of the mutations in skin, we performed immunofluorescence analyses. Notably, the amount of granular staining in the keratinocytes of affected individuals was lower in the cytoplasm but higher around the nucleus than it was in the keratinocytes of control individuals. AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone. The identification of mutations, along with the results from additional studies, defines the genetic basis of PPKP1 and provides evidence that AAGAB plays an important role in skin integrity.
authors.affiliation: Center for Rare and Genetic Skin Diseases, Department of Dermatology, Ludwig Maximilians University, 80337 Munich, Germany. kathrin.giehl@med.uni-muenchen.de
authors.forename: Kathrin A
authors.initials: KA
authors.lastname: Giehl
authors.forename: Gertrud N
authors.initials: GN
authors.lastname: Eckstein
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Pasternack
authors.forename: Silke
authors.initials: S
authors.lastname: Praetzel-Wunder
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Kerstin
authors.initials: K
authors.lastname: Seidl
authors.forename: Mike
authors.initials: M
authors.lastname: Rogers
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.forename: Lutz
authors.initials: L
authors.lastname: Langbein
authors.forename: Markus
authors.initials: M
authors.lastname: Braun-Falco
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D018389:Codon, Nonsense; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000378:metabolism; D008297:Male; D010375:Pedigree; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D012871:Skin Diseases / Q000235:genetics / Q000378:metabolism
chemical_list: C579464:AAGAB protein, human; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D018389:Codon, Nonsense; D012333:RNA, Messenger