Yunis-Varon Syndrome Is Caused by Mutations in FIG4, Encoding a Phosphoinositide Phosphatase
Yunis-Varon Syndrome Is Caused by Mutations in FIG4, Encoding a Phosphoinositide Phosphatase
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DOI：
10.1016/j.ajhg.2013.03.020
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发表时间：
2013-05-02
影响因子：
9.8
通讯作者：
Lee, Brendan H.
中科院分区：
文献类型：
--
作者：
Campeau, Philippe M.;Lenk, Guy M.;Lee, Brendan H.
尤尼斯-瓦龙综合征 (YVS) 是一种常染色体隐性遗传疾病，伴有锁骨颅骨发育不良、指异常和严重的神经系统受累。在神经元、肌肉和软骨中发现增大的液泡。通过全外显子组测序，我们在来自三个不相关家族的受影响个体中鉴定了Fig4的移码和错义突变。图4编码调节PI(3,5)P-2水平所需的磷酸肌醇磷酸酶，从而调节内体运输和自噬。在功能测定中，两种错义取代均未能纠正 Fig4-null 小鼠成纤维细胞的液泡表型。 Fig4 缺失的纯合子小鼠表现出 YVS 的特征，包括神经变性和神经元液泡增大。我们证明 Fig4-null 小鼠的骨骼较小，骨小梁体积和皮质厚度减少，并且培养的成骨细胞积累大液泡。我们的研究结果表明，FIG4 无效突变的纯合性或复合杂合性是造成 YVS 的原因，YVS 是由磷酸肌醇代谢缺陷引起的已知最严重的人类表型。相比之下，在 4J 型腓骨肌萎缩症（也是由Fig4突变引起）中，FIG4等位基因之一是低等位的，疾病仅限于周围神经系统。这种基因型表型相关性表明，FIG4 活性的缺失会导致中枢神经系统功能障碍和广泛的骨骼异常。我们的结果描述了 PI(3,5)P-2 信号在骨骼发育和维护中的作用。
Yunis-Varon syndrome (YVS) is an autosomal-recessive disorder with cleidocranial dysplasia, digital anomalies, and severe neurological involvement. Enlarged vacuoles are found in neurons, muscle, and cartilage. By whole-exome sequencing, we identified frameshift and missense mutations of FIG4 in affected individuals from three unrelated families. FIG4 encodes a phosphoinositide phosphatase required for regulation of PI(3,5)P-2 levels, and thus endosomal trafficking and autophagy. In a functional assay, both missense substitutions failed to correct the vacuolar phenotype of Fig4-null mouse fibroblasts. Homozygous Fig4-null mice exhibit features of YVS, including neurodegeneration and enlarged vacuoles in neurons. We demonstrate that Fig4-null mice also have small skeletons with reduced trabecular bone volume and cortical thickness and that cultured osteoblasts accumulate large vacuoles. Our findings demonstrate that homozygosity or compound heterozygosity for null mutations of FIG4 is responsible for YVS, the most severe known human phenotype caused by defective phosphoinositide metabolism. In contrast, in Charcot-Marie-Tooth disease type 4J (also caused by FIG4 mutations), one of the FIG4 alleles is hypomorphic and disease is limited to the peripheral nervous system. This genotypephenotype correlation demonstrates that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies. Our results describe a role for PI(3,5)P-2 signaling in skeletal development and maintenance.