title: Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB.
abstract: Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.
authors.affiliation: The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, QLD, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zankl
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Clark
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Glazov
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Addor
authors.forename: Troels
authors.initials: T
authors.lastname: Herlin
authors.forename: Chong Ae
authors.initials: CA
authors.lastname: Kim
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Leheup
authors.forename: Jim
authors.initials: J
authors.lastname: McGill
authors.forename: Steven
authors.initials: S
authors.lastname: McTaggart
authors.forename: Stephan
authors.initials: S
authors.lastname: Mittas
authors.forename: Anna L
authors.initials: AL
authors.lastname: Mitchell
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: Marie
authors.initials: M
authors.lastname: Schroeder
authors.forename: Paulien
authors.initials: P
authors.lastname: Terhal
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
mesh_terms: D001483:Base Sequence; D002348:Carpal Bones / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D059472:Exome; D005091:Exons; D005260:Female; D031845:Hajdu-Cheney Syndrome / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D051258:MafB Transcription Factor / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA / Q000379:methods; D013639:Tarsal Bones / Q000002:abnormalities*; D015533:Transcriptional Activation
chemical_list: C490407:MAFB protein, human; D051258:MafB Transcription Factor