title: Refined mapping of Naegeli-Franceschetti- Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes.
abstract: Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis are autosomal dominant ectodermal dysplasias characterized by the absence of dermatoglyphics, reticulate hyper pigmentation of the skin, hypohidrosis, and heat intolerance. Palmoplantar keratoderma, nail dystrophy, and enamel defects are common in Naegeli-Franceschetti-Jadassohn syndrome, whereas diffuse alopecia is only seen in dermatopathia pigmentosa reticularis. We studied a large Swiss family with Naegeli-Franceschetti-Jadassohn syndrome originally described by Naegeli in 1927 and assessed linkage to chromosome 17q, which was proposed to harbor the Naegeli-Franceschetti-Jadassohn syndrome gene. Our results considerably narrow the Naegeli-Franceschetti-Jadassohn syndrome gene region from 27 cM to 6 cM flanked by D17S933 and D17S934 with a maximum multipoint LOD score of 2.7 at marker locus D17S800. In addition, we studied a small family with dermatopathia pigmentosa reticularis, and our linkage data suggest that dermatopathia pigmentosa reticularis may map to the same chromosomal region. The Naegeli-Franceschetti-Jadassohn syndrome critical interval spans approximately 5.4 Mb and contains a minimum of 45 distinct genes. We scrutinized 13 new prime candidates in addition to five genes previously examined, established the genomic organization of 10 of these genes, and excluded all of them by mutation analysis. Moreover, we identified a cDNA (KRT24) encoding a new keratin protein that bears high similarity to the type I keratins and displays a unique expression profile. No pathogenic mutations were identified in this novel gene either, however. In summary, our results substantially refine the Naegeli-Franceschetti-Jadassohn syndrome region and will aid in identifying a gene that is critical for ontogenesis of multiple ectodermal tissues.
authors.affiliation: Department of Dermatology and Cutaneous Biology and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.forename: Peter
authors.initials: P
authors.lastname: Itin
authors.forename: Neil V
authors.initials: NV
authors.lastname: Whittock
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.forename: Rudolph
authors.initials: R
authors.lastname: Meyer
authors.forename: John J
authors.initials: JJ
authors.lastname: DiGiovanna
authors.forename: Sherri J
authors.initials: SJ
authors.lastname: Bale
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
mesh_terms: D000595:Amino Acid Sequence; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D018076:DNA, Complementary; D004476:Ectodermal Dysplasia / Q000235:genetics*; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D017495:Hyperpigmentation / Q000235:genetics; D007633:Keratins / Q000235:genetics*; D053530:Keratins, Type I; D007645:Keratoderma, Palmoplantar / Q000235:genetics; D008126:Lod Score; D008969:Molecular Sequence Data; D010375:Pedigree
chemical_list: D018076:DNA, Complementary; C466218:KRT24 protein, human; D053530:Keratins, Type I; D007633:Keratins