PITX2 and FOXC1 spectrum of mutations in ocular syndromes
PITX2 and FOXC1 spectrum of mutations in ocular syndromes
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DOI：
10.1038/ejhg.2012.80
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发表时间：
2012-12-01
影响因子：
5.2
通讯作者：
Semina, Elena V.
中科院分区：
文献类型：
--
作者：
Reis, Linda M.;Tyler, Rebecca C.;Semina, Elena V.
眼前节发育不全（ASD）包括影响前眼结构并与青光眼风险增加相关的广泛发育状况。在ASD病症中经常观察到各种全身异常，例如Axenoviral-Rieger综合征（ARS）和De Hauwere综合征。我们报告了76例综合征或孤立性ASD及相关疾病患者的PITX 2和FOXC 1的DNA测序和拷贝数分析。PITX 2基因突变和缺失在24例牙齿和/或脐带异常的患者中发现。7个PITX 2突变等位基因是新的，包括c.708_730del，迄今为止报道的最C-末端突变。第二个病例是PITX 2的远端上游而不是编码区的缺失，这突出了最近发现的ARS机制的重要性。在4例病例中观察到FOXC 1缺失，其中3例表现出听力和/或心脏缺陷，包括De Hauwere综合征患者;未发现FOXC 1的核苷酸突变。文献回顾发现了其他几例6p 25缺失和De Hauwere综合征特征的患者。这里提出的6p 25的1.3-Mb缺失定义了这种表型的关键区域，包括FOXC 1、FOXF 2和FOXQ 1基因。总之，在我们的队列中，PITX 2或FOXC 1破坏解释了63%的ARS和6%的其他ASD;所有受影响的患者都表现出额外的全身缺陷，PITX 2突变与牙齿和/或脐带异常以及FOXC 1与心脏和听力缺陷有很强的相关性。FOXC 1缺失也被发现与De Hauwere综合征有关。European Journal of Human Genetics（2012）20，1224-1233; doi：10.1038/ejhg.2012.80; 2012年5月9日在线发表
Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome. European Journal of Human Genetics (2012) 20, 1224-1233; doi:10.1038/ejhg.2012.80; published online 9 May 2012