Multicentric carpotarsal osteolysis syndrome is caused by only a few domain-specific mutations in MAFB, a negative regulator of RANKL-induced osteoclastogenesis

Steven Mumm, Margaret Huskey, Shenghui Duan, Deborah Wenkert, Katherine L. Madson, Gary S. Gottesman, Angela R. Nenninger, Ronald M. Laxer, William H. Mcalister, Michael P. Whyte

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish
Pages (from-to)2287-2293
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Volume164
Issue number9
DOIs
StatePublished - Sep 2014

Keywords

  • Dysplasia
  • Nephropathy
  • Osteoclast

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