Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive WNT1 mutations.
Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive WNT1 mutations.
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DOI：
10.1136/jmedgenet-2015-103476
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发表时间：
2016-06
影响因子：
4
通讯作者：
Curry CJ
中科院分区：
文献类型：
--
作者：
Aldinger KA;Mendelsohn NJ;Chung BH;Zhang W;Cohn DH;Fernandez B;Alkuraya FS;Dobyns WB;Curry CJ
WNT 1的常染色体重复性遗传突变最近被确定为严重成骨障碍（OI）的原因。1-6这一发现并没有解决模型生物中描述的Wnt 1在中后脑发育中的关键作用。7 8严重的智力和运动缺陷，注意到在4的16个家庭报告的日期，但提供的细节很少。我们回顾了一个新的和五个以前报道的WNT 1相关的OI的个人的发育结果和脑成像研究。这六个人都有脑畸形，其中五个人有明显的脑干和小脑发育不全。最近，在一系列的6篇论文中，来自16个家庭的25名个体中，WNT 1的纯合或复合杂合突变被描述为严重常染色体隐性OI的新原因。1-6在两个人的脑成像研究报告显示单侧小脑发育不全，2 4和另一个被报道有基亚里畸形1型。5然而，关于大脑和神经系统表型，仅提供了有限的数据，包括仅一张MRI图像。这是一个需要解决的重要问题，因为分泌信号蛋白的WNT家族在许多发育和稳态过程中起着关键作用。事实上，早在WNT 1突变被确定为人类骨脆性的原因之前，就在两个WNT 1突变的小鼠品系中描述了早期脑发育的显著缺陷。7 8为了检查与WNT 1突变相关的人脑表型，我们回顾了所有可用的脑成像研究，这些研究来自一个新的和五个先前报道的个体，包括一个同胞对，1-5，其中包括五个脑MRI（图1）和一个头颅CT扫描（见在线补充图S1）。我们在所有6个个体中发现了显著畸形（表1）。在三个受影响的个体中发现了海马畸形，其冠状MRI序列可用（图1 D，H，L）。6名个体中有5名的中脑（尤其是顶盖）较小，我们将其中2名个体（图1 E和在线补充图S1）评为中度，5名个体中的3名（图1 A、I、M）评为重度。值得注意的是，很少有人类疾病的报告
Autosomal recessively inherited mutations in WNT1 were recently identified as a cause of severe osteogenesis imperfecta (OI). 1–6 This finding does not address the critical role of Wnt1 in midhindbrain development that is well described in model organisms. 7 8 Severe intellectual and motor deficits were noted in 4 of 16 families reported to date, but few details were provided. We reviewed developmental outcomes and brain-imaging studies for one new and five previously reported individuals with WNT1-associated OI. All six have brain malformations, with prominent brainstem and cerebellar hypoplasia in five of these six individuals. Homozygous or compound heterozygous mutations in WNT1 were recently described as a novel cause for severe autosomal-recessive OI in 25 individuals from 16 families in a series of six papers. 1–6 Brain-imaging studies in two individuals were reported to show unilateral cerebellar hypoplasia, 2 4 and another was reported to have Chiari malformation type 1. 5 However, only limited data were presented regarding the brain and neurological phenotypes, including only a single MRI image. This is an important issue to address, as the WNT family of secreted signalling proteins play key roles in many developmental and homeostatic processes. 9 Indeed, prominent defects in early brain development were described in two mouse lines with Wnt1 mutations long before WNT1 mutations were identified as a cause of bone fragility in humans. 7 8To examine the human brain phenotype associated with mutations in WNT1, we reviewed all available brain-imaging studies from one new and five previously reported individuals including one sibling pair, 1–5 which consisted of five brain MRI (figure 1) and one cranial CT scan (see online supplementary figure S1). We found significant malformations in all six individuals (table 1). Hippocampal malformations were found in three affected individuals for whom coronal MRI sequences were available (figure 1 D, H, L). The midbrain, especially the tectum, was small in 5 of 6 individuals, which we rated as moderate in two (figure 1 E and online supplementary figure S1) and severe in three (figure 1 A, I, M) of five individuals. Notably, few human disorders have been reported