Gene dosage of the spermidine/spermine N1-acetyltransferase (SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD)
Gene dosage of the spermidine/spermine N1-acetyltransferase (SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD)
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DOI：
10.1007/s00439-002-0791-6
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发表时间：
2002-09-01
期刊：
影响因子：
5.3
通讯作者：
Seri, M
中科院分区：
文献类型：
--
作者：
Gimelli, G;Giglio, S;Seri, M
棘状毛囊十头角化症(KFSD)或西门子-1综合征是一种罕见的X连锁疾病，病因不明，影响皮肤和眼睛。虽然大多数受影响的家系都符合X连锁遗传，但KFSD似乎在临床和遗传上是不同的。到目前为止，该基因已在两个KFSD家系中定位到Xp22.13p22.2。对第一个荷兰家系中的其他重组事件的分析将该基因定位在标记DXS7163和DXS7593/DXS7105之间的大约1Mb的间隔内，而在第二个德国家系中的单倍型重构将该基因定位在先前识别的区域之外，标记DXS274的近端。我们在此报告了一例剂量敏感型性反转(DSS)和KFSD患者中存在Xp21.1p22.12重复的分子特征。该重复区域包括DAX1基因(先前被证明与DSS有关)和KFSD区间，其中编码亚精胺/精胺N-1-乙酰转移酶(SSAT)的基因位于KFSD区间。该酶催化亚精胺和精胺的N-1-乙酰化，通过多胺氧化酶的连续活性，亚精胺可以转化为亚精胺，亚精胺可以转化为腐胺。SSAT酶在小鼠模型中的过度表达导致腐胺积累和皮肤和毛发异常的表型，使人想起人类KFSD。对患者细胞内多胺代谢的分析表明，腐胺、亚精胺和精胺等代谢物的水平与SSAT基因的过度表达一致，就像在小鼠模型中一样。因此，我们认为SSAT的过度表达和随之而来的腐胺积累与KFSD的表型有关，至少在我们的先证者中是这样。
Keratosis follicularis spinulosa decalvans (KFSD) or Siemens-1 syndrome is a rare X-linked disease of unknown etiology affecting the skin and the eye. Although most affected families are compatible with X-linked inheritance, KFSD appears to be clinically and genetically heterogeneous. So far, the gene has been mapped to Xp22.13p22.2 in two extended KFSD families. Analysis of additional recombination events in the first Dutch pedigree located the gene to an interval covering approximately 1 Mb between markers DXS7163 and DXS7593/DXS7105, whereas haplotype reconstruction in the second German family positioned the gene outside the previously identified region, proximal to marker DXS274. We report here the molecular characterization of an Xp21.1p22.12 duplication present in a patient affected with dosage-sensitive sex reversal (DSS) and KFSD. The duplicated region includes both the DAX1 gene (previously demonstrated to be responsible for DSS) and the KFSD interval, in which the gene encoding spermidine/spermine N-1-acetyltransferase (SSAT) is located. This enzyme catalyzes the N-1-acetylation of spermidine and spermine and, by the successive activity of polyamine oxidase, the spermine can be converted to spermidine and the spermidine to putrescine. Overexpression of the SSAT enzyme in a mouse model results in putrescine accumulation and a phenotype with skin and hair abnormalities reminiscent of human KFSD. Analysis of polyamine metabolism in the cells of the patient indicated that the levels of metabolites such as putrescine, spermidine and spermine were consistent with the overexpression of the SSAT gene as in the murine model. Thus, we propose that overexpression of SSAT and the consequent putrescine accumulation are involved in the KFSD phenotype, at least in our propositus.