Genetics Unit, Hospital Valdecilla, 39008, Santander, Spain.
Instituto de Investigación Valdecilla (IDIVAL), 39012, Santander, Spain.
Sci Rep. 2019 Jan 24;9(1):736. doi: 10.1038/s41598-018-36859-2.
Mutations in ADNP have been recently associated with intellectual disability and autism spectrum disorder. However, the clinical features of patients with this syndrome are not fully identified, and no treatment currently exists for these patients. Here, we extended the ADNP syndrome phenotype describing skin abnormalities in both a patient with ADNP syndrome and an Adnp haploinsufficient mice. The patient displayed thin dermis, hyperkeratotic lesions in periarticular areas and delayed wound healing. Patient-derived skin keratinocytes showed reduced proliferation and increased differentiation. Additionally, detection of cell cycle markers indicated that mutant cells exhibited impaired cell cycle progression. Treatment of ADNP-deficient keratinocytes with the ADNP-derived NAP peptide significantly reduced the expression of differentiation markers. Sonography and immunofluorescence staining of epidermal layers revealed that the dermis was thinner in the patient than in a healthy control. Adnp haploinsufficient mice (Adnp) mimicked the human condition showing reduced dermal thickness. Intranasal administration of NAP significantly increased dermal thickness and normalized the levels of cell cycle and differentiation markers. Our observations provide a novel activity of the autism-linked ADNP in the skin that may serve to define the clinical phenotype of patients with ADNP syndrome and provide an attractive therapeutic option for skin alterations in these patients.
ADNP 基因突变最近与智力障碍和自闭症谱系障碍有关。然而，该综合征患者的临床特征尚未完全确定，目前这些患者尚无治疗方法。在这里，我们扩展了 ADNP 综合征表型，描述了 ADNP 综合征患者和 Adnp 杂合不足小鼠的皮肤异常。患者表现为真皮变薄、关节周围区域有角化过度病变和伤口愈合延迟。患者来源的皮肤角质形成细胞显示增殖减少和分化增加。此外，细胞周期标志物的检测表明突变细胞的细胞周期进程受损。用 ADNP 衍生的 NAP 肽处理 ADNP 缺陷角质形成细胞可显著降低分化标志物的表达。超声检查和表皮层免疫荧光染色显示患者的真皮比健康对照者薄。Adnp 杂合不足小鼠（Adnp）模拟了人类情况，表现为真皮厚度降低。鼻内给予 NAP 可显著增加真皮厚度，并使细胞周期和分化标志物的水平正常化。我们的观察结果提供了自闭症相关 ADNP 在皮肤中的新活性，这可能有助于定义 ADNP 综合征患者的临床表型，并为这些患者的皮肤改变提供有吸引力的治疗选择。
