A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts
A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts
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DOI：
10.1086/383094
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发表时间：
2004-04-01
影响因子：
9.8
通讯作者：
Reis, A
中科院分区：
文献类型：
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作者：
Zenker, M;Rauch, A;Reis, A
脑室周围结节性异位 (PVNH) 和属于耳腭指 (OPD) 谱系的一组骨骼发育不良这两种疾病是由 FLNA 突变引起的。它们被认为是相互排斥的，因为各自 FLNA 基因突变的不同推测效果，分别导致功能丧失 (PVNH) 和功能获得 (OPD)。我们在这里描述了第一例表现出 PVNH 并伴有额干骺端发育不良（OPD 谱系的骨骼发育不良）的患者。 FLNA 基因第 45 号外显子中发现了一个新的从头突变 7315C-->A。它导致两个异常转录本，一个具有点突变的全长转录本导致高度保守的亮氨酸残基 (L2439M) 的取代，而第二个缩短的转录本由于在外显子 45 中创建异位剪接供体位点而缺少 21 bp。我们认为，双表型是由两种功能不同的异常细丝蛋白 A 蛋白引起的，因此代表了等位基因功能获得和功能增强的特殊模型案例。由于单一突变事件导致的功能丧失表型。
Two disorders, periventricular nodular heterotopia (PVNH) and a group of skeletal dysplasias belonging to the oto-palato-digital (OPD) spectrum, are caused by FLNA mutations. They are considered mutually exclusive because of the different presumed effects of the respective FLNA gene mutations, leading to loss of function ( PVNH) and gain of function ( OPD), respectively. We describe here the first patient manifesting PVNH in combination with frontometaphyseal dysplasia, a skeletal dysplasia of the OPD-spectrum. A novel de novo mutation, 7315C-->A in exon 45 of the FLNA gene, was identified. It leads to two aberrant transcripts, one full-length transcript with the point mutation causing a substitution of a highly conserved leucine residue (L2439M) and a second shortened transcript lacking 21 bp due to the creation of an ectopic splice donor site in exon 45. We propose that the dual phenotype is caused by two functionally different, aberrant filamin A proteins and therefore represents an exceptional model case of allelic gain-of-function and loss-of-function phenotypes due to a single mutational event.