title: Identification of the Finnish founder mutation for diastrophic dysplasia (DTD).
abstract: Diastrophic dysplasia (DTD) is especially prevalent in Finland and the existence of a founder mutation has been previously inferred from the fact that 95% of Finnish DTD chromosomes have a rare ancestral haplotype found in only 4% of Finnish control chromosomes. Here we report the identification of the Finnish founder mutation as a GT-> GC transition (c.-26 + 2T > C) in the splice donor site of a previously undescribed 5'-untranslated exon of the diastrophic dysplasia sulfate transporter gene (DTDST); the mutation acts by severely reducing mRNA levels. Among 84 DTD families in Finland, patients carried two copies of the mutation in 69 families, one copy in 14 families, and no copies in one family. Roughly 90% of Finnish DTD chromosomes thus carry the splice-site mutation, which we have designated DTDST(Fin). Unexpectedly, we found that nine of the DTD chromosomes having the apparently ancestral haplotype did not carry DTDST(Fin), but rather two other mutations. Eight such chromosomes had an R279W mutation and one had a V340del deletion. We consider the possible implications of presence of multiple DTD mutations on this rare haplotype.
authors.affiliation: Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland. johanna.hastbacka@helsinki.fi
authors.forename: J
authors.initials: J
authors.lastname: Hästbacka
authors.forename: A
authors.initials: A
authors.lastname: Kerrebrock
authors.forename: K
authors.initials: K
authors.lastname: Mokkala
authors.forename: G
authors.initials: G
authors.lastname: Clines
authors.forename: M
authors.initials: M
authors.lastname: Lovett
authors.forename: I
authors.initials: I
authors.lastname: Kaitila
authors.forename: A
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: E S
authors.initials: ES
authors.lastname: Lander
mesh_terms: D027321:Anion Transport Proteins; D001848:Bone Diseases, Developmental / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D005091:Exons; D005387:Finland / Q000453:epidemiology; D018703:Founder Effect; D008040:Genetic Linkage; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D026901:Membrane Transport Proteins; D008957:Models, Genetic; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000076988:Sulfate Transporters
chemical_list: D027321:Anion Transport Proteins; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C089651:SLC26A2 protein, human; D000076988:Sulfate Transporters