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.

Figure 1

Typical Clinical and Radiographic Appearance of MCTO (A) Complete destruction of carpal bones with relatively well-preserved metacarpals and phalanges (individual 17.3). (B) Hand X-rays of individual 15.3 at (a) 3, (b) 8, and (c) 10 years old, respectively. Note the absence of carpal bones and progressive osteolysis of proximal end of metacarpal bones, whereas the distal end and the phalanges remain relatively well preserved.

Figure 2

Sanger Sequencing and Comparative Genomics of MAFB (Upper panel) Sanger sequencing of MAFB, demonstrating mutations in all 11 simplex cases with MCTO. Labels in bold refer to the original five probands sequenced with NGS. (Lower panel) Protein coding and comparative genomics of MAFB (derived from UCSC genome browser).

Figure 3

Sanger Sequencing and Family Trees for Families 82 and 83 (A) Family 82. (B) Family 83. Black indicates known affected and white indicates known unaffected; a question mark indicates unknown status.

Figure 4

Schematic picture of MafB, showing protein domains and positions of the observed mutations in individuals and families with MCTO