Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome
Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome
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DOI：
10.1093/hmg/7.7.1091
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发表时间：
1998-07-01
影响因子：
3.5
通讯作者：
Richards, JE
中科院分区：
文献类型：
--
作者：
Vollrath, D;Jaramillo-Babb, VL;Richards, JE
指甲-髌骨综合征是一种遗传性发育障碍，最常见的是指甲、膝盖骨和肘关节发育不良。就这些特征而言，在家族内和家族间，Escherichia coli的表型表达具有广泛的变异。其他骨骼异常，如髋关节脱位和马蹄内翻足，也有报道在一些个体与青光眼，有一个关联之间的青光眼和肾脏疾病，和青光眼和开角型青光眼（OAG），但目前还不知道是否在一个单一的基因突变导致观察到的骨骼，肾脏和眼科异常。最近，LMX 1B，一种LIM同源结构域类型的转录因子，其同源物对脊椎动物的肢体发育非常重要，被定位于9 q34处与LMX相同的一般位置。我们对4个家系的先证者基因组DNA中LMX 1B的一个大片段进行了测序，并鉴定出4个突变：2个终止密码子，1个引起移码的缺失和1个功能重要残基的错义突变。这些研究结果有助于解释高程度的变异性，在ESTA表型，并表明骨骼缺陷的ESTA是在肢体发育过程中的LMX 1B蛋白的背腹侧图案活动减少的结果，该结果进一步表明，ESTA和OAG表型的家庭研究结果从一个单一的基因，LMX 1B突变。
Nail-patella syndrome (NPS) is an inherited developmental disorder most commonly involving maldevelopment of the fingernails, kneecaps and elbow joints. NPS exhibits wide variation in phenotypic expression within and among families with respect to these features. Other skeletal abnormalities such as hip dislocation and club foot have also been reported in some individuals with NPS, There is an association between NPS and renal disease, and between NPS and open-angle glaucoma (OAG), but it is not known whether mutations in a single gene cause the observed skeletal, renal and ophthalmic abnormalities. Recently, LMX1B, a transcription factor of the LIM-homeodomain type with homologs that are important for limb development in vertebrates, was mapped to the same general location as NPS at 9q34. We sequenced a targe segment of LMX1B from the genomic DNA of probands from four families with NPS and GAG, and identified four mutations: two stop codons, a deletion causing a frameshift and a missense mutation in a functionally important residue, The presence of these putative loss-of-function mutations in the DNA of individuals with NPS indicates that haploinsufficiency of LMX1B underlies this disorder. These findings help to explain the high degree of variability in the NPS phenotype, and suggest that the skeletal defects in NPS are a result of the diminished dorsoventral patterning activity of LMX1B protein during limb development, The results further suggest that the NPS and OAG phenotypes in the families studied result from mutations in a single gene, LMX1B.