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Septo-Optic Dysplasia: From Mouse to Man

机译：视神经发育不良：从小鼠到人

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Septo-optic dysplasia (SOD) is a highly variable condition which is characterized by midline neurological abnormalities associated with pituitary hypoplasia and optic nerve hypoplasia. Recently, a novel homeobox gene, Hesx1, has been implicated in this condition. The gene encodes a 185-aminoacid transcription factor and is expressed early at gastrulation in the mouse embryo. It is initially expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Null mutant mice lacking Hesx1 exhibit a phenotype comprising variable anterior CNS defects such as a reduced prosencephalon, abnormalities in the corpus callosum and the septum pellucidum, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch with pituitary dysplasia. Since this phenotype strikingly resembled the phenotype of septo-optic dysplasia, we cloned and sequenced the human homologue HESX1 and screened for mutations in affected individuals using single-stranded conformational polymorphism analysis (SSCP). Two siblings with SOD from a highly consanguineous family were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain. This led to a loss of in vitro DNA binding. Subsequently, we have identified heterozygous mutations in HESX1 which are associated with milder pituitary phenotypes, suggesting an autosomal dominant inheritance with variable penetrance. Hence, our studies indicate a vital role for Hesx1/HESX1 in forebrain and pituitary development in mouse and man.
机译：视光发育不良（SOD）是高度可变的疾病，其特征是与垂体发育不全和视神经发育不全相关的中线神经系统异常。最近，一种新的同源盒基因Hesx1被牵涉到这种情况。该基因编码一个185个氨基酸的转录因子，并在小鼠胚胎的胃形成早期表达。它最初在预期的前脑组织中表达，但后来仅限于Rathke的囊袋（垂体前叶的原基）。缺少Hesx1的无效突变小鼠表现出一种表型，该表型包括可变的前中枢神经系统缺陷，例如前脑减少、,体和隔膜中的异常，失语症或微眼炎，嗅觉发育不良和Rathke囊中垂体发育不良的分叉。由于此表型与隔视膜发育异常的表型极为相似，因此我们对人类同源物HESX1进行了克隆和测序，并使用单链构象多态性分析（SSCP）筛选了受影响个体中的突变。来自高血缘家族的两个具有SOD的兄弟姐妹在HESX1同源域内的Arg53Cys错义突变是纯合的。这导致体外DNA结合的丧失。随后，我们发现了HESX1中的杂合突变，这些突变与较轻的垂体表型有关，表明常染色体显性遗传具有可变的渗透性。因此，我们的研究表明Hesx1 / HESX1在小鼠和人的前脑和垂体发育中起着至关重要的作用。

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