title: Gene dosage of the spermidine/spermine N(1)-acetyltransferase ( SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD).
abstract: Keratosis follicularis spinulosa decalvans (KFSD) or Siemens-1 syndrome is a rare X-linked disease of unknown etiology affecting the skin and the eye. Although most affected families are compatible with X-linked inheritance, KFSD appears to be clinically and genetically heterogeneous. So far, the gene has been mapped to Xp22.13p22.2 in two extended KFSD families. Analysis of additional recombination events in the first Dutch pedigree located the gene to an interval covering approximately 1 Mb between markers DXS7163 and DXS7593/DXS7105, whereas haplotype reconstruction in the second German family positioned the gene outside the previously identified region, proximal to marker DXS274. We report here the molecular characterization of an Xp21.1p22.12 duplication present in a patient affected with dosage-sensitive sex reversal (DSS) and KFSD. The duplicated region includes both the DAX1 gene (previously demonstrated to be responsible for DSS) and the KFSD interval, in which the gene encoding spermidine/spermine N(1)-acetyltransferase ( SSAT) is located. This enzyme catalyzes the N(1)-acetylation of spermidine and spermine and, by the successive activity of polyamine oxidase, the spermine can be converted to spermidine and the spermidine to putrescine. Overexpression of the SSAT enzyme in a mouse model results in putrescine accumulation and a phenotype with skin and hair abnormalities reminiscent of human KFSD. Analysis of polyamine metabolism in the cells of the patient indicated that the levels of metabolites such as putrescine, spermidine and spermine were consistent with the overexpression of the SSAT gene as in the murine model. Thus, we propose that overexpression of SSAT and the consequent putrescine accumulation are involved in the KFSD phenotype, at least in our propositus.
authors.affiliation: Laboratorio di Citogenetica, Istituto G. Gaslini, L.go G.Gaslini 5, 16148 Genoa, Italy. giorgiogimelli@ospedale-gaslini.ge.it
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gimelli
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Suvikki
authors.initials: S
authors.lastname: Suppola
authors.forename: Roberto
authors.initials: R
authors.lastname: Cusano
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
authors.forename: Rosanna
authors.initials: R
authors.lastname: Gatti
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
mesh_terms: D000123:Acetyltransferases / Q000235:genetics*; D000818:Animals; D002648:Child; D002871:Chromosome Banding; D041321:Chromosomes, Human, X / Q000235:genetics*; D007644:Darier Disease / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D006059:Gonadal Dysgenesis / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D010375:Pedigree; D010641:Phenotype; D011700:Putrescine / Q000378:metabolism; D013577:Syndrome; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D011700:Putrescine; D000099228:Diamine N-Acetyltransferase