title: Multicentric carpotarsal osteolysis syndrome is caused by only a few domain-specific mutations in MAFB, a negative regulator of RANKL-induced osteoclastogenesis.
abstract: Multicentric carpotarsal osteolysis syndrome (MCTO), an autosomal dominant disorder that often presents sporadically, features carpal-tarsal lysis frequently followed by nephropathy and renal failure. In 2012, mutations in the single-exon gene MAFB were reported in 13 probands with MCTO. MAFB is a negative regulator of RANKL-mediated osteoclastogenesis. We studied nine MCTO patients (seven sporadic patients and one affected mother and son) for MAFB mutation. We PCR-amplified and selectively sequenced the MAFB region that contains the transactivation domain in this 323 amino acid protein, where mutations were previously reported for MCTO. We found five different heterozygous missense defects among eight probands: c.176C > T, p.Pro59Leu; c.185C > T, p.Thr62Ile; c.206C > T, p.Ser69Leu (four had this defect); c.209C > T, p.Ser70Leu; and c.211C > T, p.Pro71Ser. All 5 mutations are within a 13 amino acid stretch of the transactivation domain. Four were identical to the previously reported mutations. Our unique mutation (c.185C > T, p.Thr62Ile) involved the same domain. DNA available from seven parents of the seven sporadic patients did not show their child's MAFB mutation. The affected mother and son had an identical defect. Hence, the mutations for 7/8 probands were suspected to have arisen spontaneously as there was no history of features of MCTO in either parent. Penetrance of MCTO seemed complete. Lack of nonsense or other truncating mutations suggested a dominant-negative pathogenesis. Our findings indicate that only a few transactivation domain-specific mutations within MAFB cause MCTO.
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri; Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri.
authors.forename: Steven
authors.initials: S
authors.lastname: Mumm
authors.forename: Margaret
authors.initials: M
authors.lastname: Huskey
authors.forename: Shenghui
authors.initials: S
authors.lastname: Duan
authors.forename: Deborah
authors.initials: D
authors.lastname: Wenkert
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Madson
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gottesman
authors.forename: Angela R
authors.initials: AR
authors.lastname: Nenninger
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Laxer
authors.forename: William H
authors.initials: WH
authors.lastname: McAlister
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006225:Hand / Q000000981:diagnostic imaging; D006801:Humans; D051258:MafB Transcription Factor / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010010:Osteoclasts / Q000473:pathology*; D010012:Osteogenesis / Q000235:genetics*; D010014:Osteolysis / Q000000981:diagnostic imaging / Q000235:genetics*; D053245:RANK Ligand / Q000378:metabolism*; D011859:Radiography; D055815:Young Adult
chemical_list: C490407:MAFB protein, human; D051258:MafB Transcription Factor; D053245:RANK Ligand
keywords: dysplasia; nephropathy; osteoclast