家养梅花鹿疑似皮肤松弛症的研究
摘要
皮肤松弛症（Cutis laxa，CL）是一组遗传性或获得性结缔组织疾病，以全身或局部皮肤不正常的松弛、下垂、次弹性为共同特征。典型的CL患者的皮肤可以很容易地拉离底层组织，松开后不能短时间恢复到其原始位置。该病罕见发生，主要见于人类，遗传性发病比率为1-2:400000，获得性的发病率更低。冗长的皮肤通常在颈部、手部、及腹股沟最明显，也可以在脸上看到，产生一种过早衰老的面容。目前对人皮肤松弛症的诊断主要采取体格检查、光镜电镜观察和相关基因检测的方法。尚未见其它动物患有皮肤松弛症的诊断研究报道。我们首次在吉林梅花鹿群体中观察到3只雄性成年梅花鹿4岁后颈后部皮肤出现非常明显的松弛下垂现象。松弛的皮肤弹力不强，到发情季节颈后部皮肤松弛现象更加严重。现场没有观察到这三只梅花鹿出现呼吸、骨骼或生殖泌尿系统的异常现象，松弛的皮肤表面没有伤痕，并且这种梅花鹿产茸量较高（三只均为种公鹿）。其中一只公鹿的同父异母兄弟（非三只梅花鹿之一）也具有相同的皮肤松弛现象。我们对颈背部皮肤松弛梅花鹿进行了流行病学调查，对已发现的三只梅花鹿进行了皮肤组织光镜和电子显微镜观察，采用分子生物学技术检验了弹力基因（elastin, ELN）和Fibulin-5基因突变情况，并从免疫组化和荧光定量角度分析了ELN、Fibulin-5和赖氨酰氧化酶（lysyloxidase, LOX）基因表达情况。结果如下：
1、流行病学调查表明，仅在个别家养梅花鹿品种鹿群中发现有极个别梅花鹿个体表现颈背部皮肤松弛现象；该性状有家系发生倾向，可能是一种常染色体隐性遗传性状；该性状对公鹿健康和生产性能没有不利影响。
2、光镜观察表明，正常梅花鹿皮肤切片弹性纤维排列规则致密，呈波浪状，染色均匀，呈多层相间分布，内膜弹力纤维清晰。颈部皮肤松弛的梅花鹿的真皮弹力纤维和胶原纤维遭到破坏，弹性纤维严重发育不全，出现分离、断裂现象，排列紊乱、呈不规则状。胶原纤维表现为严重的稀疏。
3、透射电镜观察表明，正常梅花鹿电镜下可清楚地显示大量的弹力纤维和丰富的胶原纤维。弹力纤维呈棒状或树枝状，中央部由大量无定形的均质状弹性蛋白和微纤维组成，电子密度较低；外周部为短微原纤维，呈短丛毛状，电子密度较高。皮肤松弛症梅花鹿皮肤真皮层出现较多的纤维变性区，弹力纤维减少，外形不规则，染色较浅且不均匀，有些区域弹力纤维很少，甚至呈灶状缺失。内部电子密度减低且不均匀。弹性纤维的无定形组分有很多分支和碎片。胶原纤维排列紊乱，稀疏不一，肿胀、断裂。
4、基因突变分析表明，具有颈背部皮肤松弛现象的大0号梅花鹿的Fibulin-5基因发现3处同义突变：c.601C>G、c.1030C>T和c.1081C>T；具有颈部皮肤松弛现象的33号梅花鹿Fibulin-5基因也发生了一处与大0号梅花鹿同样的同义突变：c.601C>G。两只鹿三处突变都没有改变相应氨基酸序列。
5、免疫组化研究结果表明，梅花鹿ELN基因在颈部皮肤组织切片表达于细胞外基质，对照组梅花鹿呈强阳性表达，而皮肤松弛梅花鹿呈弱阳性表达。
梅花鹿Fibulin-5基因在后颈部皮肤组织切片中也表达于细胞外基质，颈部皮肤松弛梅花鹿大0号、33号和79号梅花鹿的表达强度明显低于对照组梅花鹿。
梅花鹿LOX基因在后颈部皮肤切片中表达于细胞外基质，对照组阳性表达为深黄色，分布较皮肤松弛组密集，明显高于背景颜色，皮肤松弛组LOX基因表达稀疏，呈低表达状态。
6、实时荧光定量PCR研究表明，与对照组梅花鹿ELN基因mRNA表达水平相比，皮肤松弛梅花鹿ELN基因mRNA表达有明显的增高趋势。皮肤松弛梅花鹿Fibulin-5基因mRNA表达量升高，而33号鹿与对照组梅花鹿Fibulin-5基因表达水平不相上下，大0号鹿升高较明显。皮肤松弛梅花鹿LOX1基因mRNA表达水平较稳定，与对照组梅花鹿表达量几乎相同。
综上所述，本研究中3只梅花鹿颈部皮肤松弛现象是一种皮肤松弛症症状，该症的发生可能与ELN基因、Fibulin-5基因和LOX1基因在皮肤外基质中的弱表达有关，其中大0号梅花鹿可能患先天性皮肤松弛症，但其遗传方式和导致该症状发生的相关基因突变，尚需进一步进行后裔鉴定和DNA分析研究确定。
Cutis laxa is a heterogeneous group of rare inherited and acquired connective tissue disorders,whose common feature is occurrence of loose and redundant skin with decreased elasticity. Thetypical clinical feature of CL patient is that the skin can be easily pulled away from the underlyingtissue, but it can’t return to its original position after the release in a short time. The incidence rateof the rare hereditary disease was1-2:400000, and acquired CL have a lower incidence. We firstobserved obvious sagging skin disease in the neck of three adult male deer. To confirm thediagnosis, the skin histology was studied by light and electron microscopy, the molecular biologywas examined by sequencing the ELN and Fibulin-5gene mutation, immunohistochemistry andReal-time fluorescent quantitative PCR was used to study the ELN and Fibulin-5gene expression.The results were as follows:
1Histologic examination of skin sections showed destruction morphology of elastin fbersand collagen fibers, the elastic fibers appeared severe hypoplasia with isolated, disorganized, smallfragmented and clumped appearance in the reticular dermis of cutis laxa deer. The collagen fibersshowed severe sparse.
2In the reticular dermis of cutis laxa deer, many elastin fibres were seen to be highlyabnormal in both shape and electron density. Some fibres showed a loosely organized, missing ordamaged appearance. Situated within a loose matrix of widely dispersed collagen bundles, theyshowed many amorphous component in the regions of the elastic material and the separate elasticglobules. There are many branches and debris in amorphous component of elastic fibers.
3Three synonymous mutation, which was not present in healthy control sika deer, c.601C>G,c.1030C>T and c.1081C>T were identified in No.0of Fibulin-5gene. Also, there was asynonymous mutation occurring at c.601C> G in No.33cutis laxa deer.
4The ELN, Fibulin-5and LOX1gene in the neck skin of sika deer were expressed in theextracellular matrix. ELN was strongly expressed in the control group and weakly expressed incutis laxa sika deer; The intensity of Fibulin-5expression was significantly lower than the control group; LOX1was distributed densely with positive expression in the control group compared tocutis laxa deer, which expressed sparse and low.
5The ELN mRNA expression level of cutis laxa sika deer was significantly higher than thatof control group. The Fibulin-5expression levels of cutis laxa sika deer was increased overall,however, the expression levels of No.33and control group was similar, No.0deer increased moresignificantly. LOX1expressed stably in cutis laxa sika deer, and showed almost the sameexpression with the control group.
1、流行病学调查表明，仅在个别家养梅花鹿品种鹿群中发现有极个别梅花鹿个体表现颈背部皮肤松弛现象；该性状有家系发生倾向，可能是一种常染色体隐性遗传性状；该性状对公鹿健康和生产性能没有不利影响。
2、光镜观察表明，正常梅花鹿皮肤切片弹性纤维排列规则致密，呈波浪状，染色均匀，呈多层相间分布，内膜弹力纤维清晰。颈部皮肤松弛的梅花鹿的真皮弹力纤维和胶原纤维遭到破坏，弹性纤维严重发育不全，出现分离、断裂现象，排列紊乱、呈不规则状。胶原纤维表现为严重的稀疏。
3、透射电镜观察表明，正常梅花鹿电镜下可清楚地显示大量的弹力纤维和丰富的胶原纤维。弹力纤维呈棒状或树枝状，中央部由大量无定形的均质状弹性蛋白和微纤维组成，电子密度较低；外周部为短微原纤维，呈短丛毛状，电子密度较高。皮肤松弛症梅花鹿皮肤真皮层出现较多的纤维变性区，弹力纤维减少，外形不规则，染色较浅且不均匀，有些区域弹力纤维很少，甚至呈灶状缺失。内部电子密度减低且不均匀。弹性纤维的无定形组分有很多分支和碎片。胶原纤维排列紊乱，稀疏不一，肿胀、断裂。
4、基因突变分析表明，具有颈背部皮肤松弛现象的大0号梅花鹿的Fibulin-5基因发现3处同义突变：c.601C>G、c.1030C>T和c.1081C>T；具有颈部皮肤松弛现象的33号梅花鹿Fibulin-5基因也发生了一处与大0号梅花鹿同样的同义突变：c.601C>G。两只鹿三处突变都没有改变相应氨基酸序列。
5、免疫组化研究结果表明，梅花鹿ELN基因在颈部皮肤组织切片表达于细胞外基质，对照组梅花鹿呈强阳性表达，而皮肤松弛梅花鹿呈弱阳性表达。
梅花鹿Fibulin-5基因在后颈部皮肤组织切片中也表达于细胞外基质，颈部皮肤松弛梅花鹿大0号、33号和79号梅花鹿的表达强度明显低于对照组梅花鹿。
梅花鹿LOX基因在后颈部皮肤切片中表达于细胞外基质，对照组阳性表达为深黄色，分布较皮肤松弛组密集，明显高于背景颜色，皮肤松弛组LOX基因表达稀疏，呈低表达状态。
6、实时荧光定量PCR研究表明，与对照组梅花鹿ELN基因mRNA表达水平相比，皮肤松弛梅花鹿ELN基因mRNA表达有明显的增高趋势。皮肤松弛梅花鹿Fibulin-5基因mRNA表达量升高，而33号鹿与对照组梅花鹿Fibulin-5基因表达水平不相上下，大0号鹿升高较明显。皮肤松弛梅花鹿LOX1基因mRNA表达水平较稳定，与对照组梅花鹿表达量几乎相同。
综上所述，本研究中3只梅花鹿颈部皮肤松弛现象是一种皮肤松弛症症状，该症的发生可能与ELN基因、Fibulin-5基因和LOX1基因在皮肤外基质中的弱表达有关，其中大0号梅花鹿可能患先天性皮肤松弛症，但其遗传方式和导致该症状发生的相关基因突变，尚需进一步进行后裔鉴定和DNA分析研究确定。
Cutis laxa is a heterogeneous group of rare inherited and acquired connective tissue disorders,whose common feature is occurrence of loose and redundant skin with decreased elasticity. Thetypical clinical feature of CL patient is that the skin can be easily pulled away from the underlyingtissue, but it can’t return to its original position after the release in a short time. The incidence rateof the rare hereditary disease was1-2:400000, and acquired CL have a lower incidence. We firstobserved obvious sagging skin disease in the neck of three adult male deer. To confirm thediagnosis, the skin histology was studied by light and electron microscopy, the molecular biologywas examined by sequencing the ELN and Fibulin-5gene mutation, immunohistochemistry andReal-time fluorescent quantitative PCR was used to study the ELN and Fibulin-5gene expression.The results were as follows:
1Histologic examination of skin sections showed destruction morphology of elastin fbersand collagen fibers, the elastic fibers appeared severe hypoplasia with isolated, disorganized, smallfragmented and clumped appearance in the reticular dermis of cutis laxa deer. The collagen fibersshowed severe sparse.
2In the reticular dermis of cutis laxa deer, many elastin fibres were seen to be highlyabnormal in both shape and electron density. Some fibres showed a loosely organized, missing ordamaged appearance. Situated within a loose matrix of widely dispersed collagen bundles, theyshowed many amorphous component in the regions of the elastic material and the separate elasticglobules. There are many branches and debris in amorphous component of elastic fibers.
3Three synonymous mutation, which was not present in healthy control sika deer, c.601C>G,c.1030C>T and c.1081C>T were identified in No.0of Fibulin-5gene. Also, there was asynonymous mutation occurring at c.601C> G in No.33cutis laxa deer.
4The ELN, Fibulin-5and LOX1gene in the neck skin of sika deer were expressed in theextracellular matrix. ELN was strongly expressed in the control group and weakly expressed incutis laxa sika deer; The intensity of Fibulin-5expression was significantly lower than the control group; LOX1was distributed densely with positive expression in the control group compared tocutis laxa deer, which expressed sparse and low.
5The ELN mRNA expression level of cutis laxa sika deer was significantly higher than thatof control group. The Fibulin-5expression levels of cutis laxa sika deer was increased overall,however, the expression levels of No.33and control group was similar, No.0deer increased moresignificantly. LOX1expressed stably in cutis laxa sika deer, and showed almost the sameexpression with the control group.
引文
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