Fong Keith S K, Cooper Tiffiny Baring, Drumhiller Wallace C, Somponpun S Jack, Yang Shiming, Ernst Thomas, Chang Linda, Lozanoff Scott
Department of Anatomy, Biochemistry, and Physiology, University of Hawaii, John A. Burns School of Medicine, Honolulu, Hawaii 96813, USA.
Birth Defects Res A Clin Mol Teratol. 2012 Feb;94(2):102-13. doi: 10.1002/bdra.22878. Epub 2012 Jan 13.
Intracranial lipomas are rare, but 45% of them occur along the midline cisterns between the hemispheres and are often associated with corpus callosum hypoplasia and craniofacial defects. They are difficult to detect as they are generally asymptomatic and visible by MRI or by postmortem examination. The exact cause of these interhemispheric lipomas is not known, but they arise from a developmental defect resulting in the maldifferentiation of mesenchymal cells into mesodermal derivatives that are not normally present. We have identified a new mouse mutant called tuft, exhibiting a forebrain, intracranial lipoma with midline craniofacial defects resembling frontonasal dysplasia (FND) that arose spontaneously in our wild-type 3H1 colony. The tuft trait seems to be transmitted in recessive fashion, but approximately 80% less frequent than the expected Mendelian 25%, due to either incomplete penetrance or prenatal lethality. MRI and histologic analysis revealed that the intracranial lipoma occurred between the hemispheres and often protruded through the sagittal suture. We also observed a lesion at the lamina terminalis (LT) that may indicate improper closure of the anterior neuropore. We have mapped the tuft trait to within an 18 cM region on mouse chromosome 10 by microsatellite linkage analysis and identified several candidate genes involved with craniofacial development and cellular differentiation of adipose tissue. Tuft is the only known mouse model for midline craniofacial defects with an intracranial lipoma. Identifying the gene(s) and mutation(s) causing this early developmental defect will help us understand the pathogenesis of FND and related craniofacial disorders.
颅内脂肪瘤很罕见，但其中45%发生在半球间脑池，常与胼胝体发育不全及颅面缺陷相关。它们通常无症状，难以被检测到，不过通过磁共振成像（MRI）或尸检可见。这些半球间脂肪瘤的确切病因尚不清楚，但它们源于一种发育缺陷，导致间充质细胞异常分化为正常情况下不存在的中胚层衍生物。我们鉴定出一种名为tuft的新小鼠突变体，其表现出前脑颅内脂肪瘤，伴有类似鼻额发育异常（FND）的中线颅面缺陷，该突变体在我们的野生型3H1群体中自发出现。tuft性状似乎以隐性方式遗传，但由于不完全显性或产前致死，其出现频率比预期的孟德尔遗传25%低约80%。MRI和组织学分析显示，颅内脂肪瘤发生在半球间，常通过矢状缝突出。我们还在终板（LT）处观察到一个病变，这可能表明前神经孔闭合不当。通过微卫星连锁分析，我们已将tuft性状定位到小鼠10号染色体上一个18厘摩（cM）的区域内，并鉴定出几个与颅面发育及脂肪组织细胞分化相关的候选基因。tuft是唯一已知的具有颅内脂肪瘤的中线颅面缺陷小鼠模型。确定导致这种早期发育缺陷的基因和突变，将有助于我们了解FND及相关颅面疾病的发病机制。
