Truncation of POC1A associated with short stature and extreme insulin resistance.
Truncation of POC1A associated with short stature and extreme insulin resistance.
复制标题
POC1A的截断与矮小的身材和极端胰岛素抵抗有关。
DOI：
10.1530/jme-15-0090
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发表时间：
2015-10
影响因子：
3.5
通讯作者：
Barroso I
中科院分区：
文献类型：
--
作者：
Chen JH;Segni M;Payne F;Huang-Doran I;Sleigh A;Adams C;UK10K Consortium;Savage DB;O'Rahilly S;Semple RK;Barroso I
我们描述了一名女性先证者，患有原始侏儒症、骨骼发育不良、面部畸形、极度血脂异常、胰岛素抵抗和脂肪肝，与 POC1A 中的一种新型纯合移码突变相关，预计会影响该基因的三种蛋白质产物中的两种。 POC1A 编码一种与整个细胞周期中心粒相关的蛋白质，并与有丝分裂纺锤体和初级纤毛功能有关。影响 POC1A 所有亚型的两个纯合突变最近被认为与原始侏儒症的类似综合征有关，尽管没有描述详细的代谢表型。我们描述的先证者的原代细胞在有丝分裂期间表现出增加的中心体扩增和多极纺锤体形成，但显示出正常的DNA含量，反对有丝分裂跳跃、分裂失败或细胞融合。尽管有证据表明具有多余中心体的细胞中 DNA 损伤增加，但没有检测到非整倍性。有丝分裂纺锤体和初级纤毛中广泛的中心体聚集减轻了中心体扩增的后果，并且初级纤毛形成正常。尽管需要对 POC1A 突变患者进行进一步的代谢研究，但我们建议将 POC1A 添加到 ALMS1 和 PCNT 中，作为中心体或中心粒周围蛋白的例子，其功能障碍会导致极端血脂异常胰岛素抵抗。对这些分子缺陷与脂肪组织功能障碍之间联系的进一步研究可能会深入了解对代谢健康至关重要的脂肪组织维持和再生机制。
We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Two homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described. Primary cells from the proband we describe exhibited increased centrosome amplification and multipolar spindle formation during mitosis, but showed normal DNA content, arguing against mitotic skipping, cleavage failure or cell fusion. Despite evidence of increased DNA damage in cells with supernumerary centrosomes, no aneuploidy was detected. Extensive centrosome clustering both at mitotic spindles and in primary cilia mitigated the consequences of centrosome amplification, and primary ciliary formation was normal. Although further metabolic studies of patients with POC1A mutations are warranted, we suggest that POC1A may be added to ALMS1 and PCNT as examples of centrosomal or pericentriolar proteins whose dysfunction leads to extreme dyslipidaemic insulin resistance. Further investigation of links between these molecular defects and adipose tissue dysfunction is likely to yield insights into mechanisms of adipose tissue maintenance and regeneration that are critical to metabolic health.