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 is caused by only a few domain-specific mutations in MAFB, a negative regulator of RANKL-induced osteoclastogenesis.
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DOI：
10.1002/ajmg.a.36641
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Whyte MP
中科院分区：
文献类型：
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作者：
Mumm S;Huskey M;Duan S;Wenkert D;Madson KL;Gottesman GS;Nenninger AR;Laxer RM;McAlister WH;Whyte MP
多中心腕跗骨溶解综合征 (MCTO) 是一种常散发的常染色体显性遗传疾病，其特征是腕跗骨溶解，经常伴有肾病和肾衰竭。 2012年，13名MCTO先证者的单外显子基因MAFB发生突变。 MAFB 是 RANKL 介导的破骨细胞生成的负调节因子。我们研究了 9 名 MCTO 患者（7 名散发患者和一名受影响的母子）的 MAFB 突变。我们对包含该 323 个氨基酸蛋白中的反式激活结构域的 MAFB 区域进行 PCR 扩增并选择性测序，之前报道了 MCTO 的突变。我们在8个先证者中发现了5个不同的杂合错义缺陷：c.176C>T，p.Pro59Leu； c.185C>T，p.Thr62Ile； c.206C>T，p.Ser69Leu（4个有此缺陷）； c.209C>T，p.Ser70Leu；和c.211C>T，p.Pro71Ser。所有 5 个突变均位于反式激活结构域的 13 个氨基酸段内。其中四个与之前报道的突变相同。我们独特的突变（c.185C>T，p.Thr62Ile）涉及相同的结构域。 7 名散发患者的 7 名父母的 DNA 未显示他们孩子的 MAFB 突变。受影响的母亲和儿子有相同的缺陷。因此，7/8 先证者的突变被怀疑是自发发生的，因为父母双方都没有 MCTO 特征的病史。 MCTO 的渗透似乎已完成。缺乏无义突变或其他截短突变表明显性失活发病机制。我们的研究结果表明，MAFB 内只有少数反式激活域特异性突变会导致 MCTO。
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 9 MCTO patients (7 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 5 different heterozygous missense defects among 8 probands: c.176C>T, p.Pro59Leu; c.185C>T, p.Thr62Ile; c.206C>T, p.Ser69Leu (4 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 7 parents of the 7 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.