Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans.
Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans.
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DOI：
10.1172/jci91913
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发表时间：
2017-05-01
期刊：
影响因子：
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通讯作者：
Achermann JC
中科院分区：
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作者：
Buonocore F;Kühnen P;Suntharalingham JP;Del Valle I;Digweed M;Stachelscheid H;Khajavi N;Didi M;Brady AF;Blankenstein O;Procter AM;Dimitri P;Wales JKH;Ghirri P;Knöbl D;Strahm B;Erlacher M;Wlodarski MW;Chen W;Kokai GK;Anderson G;Morrogh D;Moulding DA;McKee SA;Niemeyer CM;Grüters A;Achermann JC
众所周知，体细胞基因组变化可以影响癌症的表型，但适应性变化在发育障碍中的作用尚不清楚。在这里，我们使用下一代测序方法来鉴定 8 名患有称为 MIRAGE 综合征的多系统疾病的儿童中含有不育 α 基序结构域的蛋白 9（SAMD9，位于染色体 7q21.2）的从头杂合突变，其特征是宫内生长受限（IUGR），伴有性腺、肾上腺和骨髓衰竭，易患 感染率高，死亡率高。这些突变导致生长抑制产物 SAMD9 的功能获得。通过单体 7 (–7) 的发展、7q (7q–) 的缺失和 SAMD9 中的继发性体细胞功能丧失（无义和移码）突变，突变 SAMD9 逐渐丧失，从而挽救了突变 SAMD9 蛋白在骨髓中的生长限制作用，并与生存时间延长相关。然而，2 名 –7 和 7q– 患者出现骨髓增生异常综合征，很可能是由于相关 7q21.2 基因的单倍体不足所致。总而言之，这些发现提供了强有力的证据，表明特定组织中可能发生进行性体细胞变化，并随后改变疾病表型并影响生存。这种组织特异性适应性可能是比目前认识到的更常见的改变人类遗传条件表达的机制。
It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.