title: Mesomelia-synostoses syndrome results from deletion of SULF1 and SLCO5A1 genes at 8q13.
abstract: Mesomelia-synostoses syndrome (MSS) or mesomelic dysplasia with acral synostoses Verloes-David-Pfeiffer type is a rare autosomal-dominant disorder characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations. So far, five patients in four unrelated families have been reported worldwide with MMS. By using whole-genome oligonucleotide array CGH, we have identified an interstitial deletion at 8q13 in all patients. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1, encoding the heparan sulfate 6-O-endosulfatase 1, and SLCO5A1, encoding the solute carrier organic anion transporter family member 5A1. SULF1 acts as a regulator of numerous growth factors in skeletal embryonic development whereas the function of SLCO5A1 is yet unknown. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Real-time quantitative RT-PCR analysis showed the highest levels of SULF1 transcripts in human osteoblasts and cartilage whereas SLCO5A1 was highly expressed in human fetal and adult brain and heart. Our results strongly suggest that haploinsufficiency of SULF1 contributes to this mesomelic chondrodysplasia, highlighting the critical role of endosulfatase in human skeletal development. Codeletion of SULF1 and SLCO5A1--which does not result from a low-copy repeats (LCRs)-mediated recombination event in at least two families--was found in all patients, so we suggest that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS.
authors.affiliation: CHU Nantes, Service de Génétique Médicale, Nantes, F44093, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.forename: Olivier
authors.initials: O
authors.lastname: Pichon
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.forename: Debra
authors.initials: D
authors.lastname: Day-Salvatore
authors.forename: Antoine
authors.initials: A
authors.lastname: Hamel
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Siwicka
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.forename: Lena
authors.initials: L
authors.lastname: Kjellén
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kraus
authors.forename: Jules G
authors.initials: JG
authors.lastname: Leroy
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D047108:Embryonic Development; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D027361:Organic Anion Transporters / Q000096:biosynthesis / Q000235:genetics*; D010375:Pedigree; D015238:Sulfotransferases / Q000096:biosynthesis / Q000235:genetics*; D013577:Syndrome; D013580:Synostosis / Q000235:genetics*; D038062:Upper Extremity Deformities, Congenital / Q000235:genetics*
chemical_list: D027361:Organic Anion Transporters; C551029:SLCO5A1 protein, human; C470791:SULF1 protein, human; D015238:Sulfotransferases