Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet-Biedl syndrome with situs inversus and insertional polydactyly
Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet-Biedl syndrome with situs inversus and insertional polydactyly
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DOI：
10.1136/jmedgenet-2012-100737
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发表时间：
2012-05-01
影响因子：
4
通讯作者：
Dollfus, Helene
中科院分区：
文献类型：
--
作者：
Marion, Vincent;Stutzmann, Fanny;Dollfus, Helene
研究背景Bardet-Biedl综合征（BBS）是一种隐性遗传高度异质性的睫状体病，主要表现为多指（趾）畸形、视网膜色素变性、肥胖、认知功能障碍和肾功能障碍。到目前为止已知的16 BBS基因是隐含在初级纤毛相关cellular pathways.Methods和结果单核苷酸多态性（SNP）阵列分析，然后由外显子组测序进行了诊断与BBS不寻常的发展功能，即原位inversus和插入多指（趾）的近亲家庭。鉴定了LZTFL 1中的纯合5 bp缺失（NM_020347.2：c.402- 406 del，p.Pro136ThrfsX5）。在患者的成纤维细胞中没有发现LZTFL 1转录本，也没有检测到蛋白质。对患者的成纤维细胞进行的音速刺猬（Shh）途径分析显示Smo显著增加。Patched 1和下游靶点GLI 2也被上调，表明在LZTFL 1缺失的情况下Shh信号通路整体上被大量激活。结论LZTFL 1编码人亮氨酸拉链转录因子L1，最近被证明是BBSome纤毛运输和Shh信号通路的重要负调控因子。这项研究表明，LZTFL 1的缺乏导致BBS表型与细胞Shh功能障碍相关的发育异常增强。LZTFL 1是一个新的BBS基因（BBS 17）。
Background Bardet-Biedl Syndrome (BBS) is an emblematic recessive genetically highly heterogeneous ciliopathy characterised mainly by polydactyly, retinitis pigmentosa, obesity, cognitive impairment, and kidney dysfunction. The 16 BBS genes known to date are implied in the primary cilia related cellular pathways.Methods and results Single nucleotide polymorphism (SNP) array analysis followed by exome sequencing was performed in a consanguineous family diagnosed with BBS with unusual developmental features, namely situs inversus and insertional polydactyly. A homozygous 5 bp deletion (NM_020347.2:c.402-406del, p.Pro136ThrfsX5) in LZTFL1 was identified. No LZTFL1 transcript was found in the patient's fibroblasts and no protein could be detected. The sonic hedgehog (Shh) pathway analysis conducted on the patient's fibroblast showed a significant increase in Smo. Patched1 as well as the downstream target GLI2 were also found to be upregulated, indicating an overall massive activation of the Shh signalling in the absence of LZTFL1.Conclusion LZTFL1, encoding the human leucine zipper transcription factor like 1, has been recently shown to be an important negative regulator of BBSome ciliary trafficking and Shh signalling. This study shows that absence of LZTFL1 leads to a BBS phenotype with enhanced developmental abnormalities associated with cellular Shh dysfunction. LZTFL1 is a novel BBS gene (BBS17).