Multicentric carpotarsal osteolysis syndrome is caused by only a few domain-specific mutations in MAFB, a negative regulator of RANKL-induced osteoclastogenesis.
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.
['Mumm|Steven|S|', 'Huskey|Margaret|M|', 'Duan|Shenghui|S|', 'Wenkert|Deborah|D|', 'Madson|Katherine L|KL|', 'Gottesman|Gary S|GS|', 'Nenninger|Angela R|AR|', 'Laxer|Ronald M|RM|', 'McAlister|William H|WH|', 'Whyte|Michael P|MP|']
D000293:Adolescent D000328:Adult D001483:Base Sequence D002648:Child D002675:Child, Preschool D015331:Cohort Studies D005260:Female D006225:Hand D006801:Humans D051258:MafB Transcription Factor D008297:Male D008969:Molecular Sequence Data D009154:Mutation D010010:Osteoclasts D010012:Osteogenesis D010014:Osteolysis D053245:RANK Ligand D011859:Radiography D055815:Young Adult
nephropathy dysplasia osteoclast