PDF(Pubmed)
Abstract：
BACKGROUND: PRDM12 polyalanine tract expansions cause two different disorders: midfacial toddler excoriation syndrome (MiTES; itch with normal pain sensation associated with 18 homozygous alanines (18A); and congenital insensitivity to pain (CIP) with normal itch associated with 19 homozygous alanines (19A). Knowledge of the phenotype, genotype and disease mechanism of MiTES is incomplete. Why 18A vs. 19A PRDM12 can cause almost opposite phenotypes is unknown; no other polyalanine or polyglutamine tract expansion disease causes two such disparate phenotypes.
OBJECTIVE: To assess the genotype and phenotype of nine new, nine atypical and six previously reported patients diagnosed with MiTES.
METHODS: Using cell lines with homozygous PR domain zinc finger protein 12 (PRDM12) containing 12 alanines (12A; normal), 18A (MiTES) and 19A (CIP), we examined PRDM12 aggregation and subcellular localization by image-separation confocal microscopy and subcellular fractionation Western blotting.
RESULTS: MiTES presents in the first year of life; in all cases the condition regresses over the first decade, leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12 CIP are rarely found. The genotype-phenotype study of the PRDM12 polyalanine tract shows that having 7-15 alanines is normal; 16-18 alanines is associated with MiTES; 19 alanines leads to CIP; and no clinically atypical cases of MiTES had a polyalanine tract expansion. PRDM12 aggregation and subcellular localization differed significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein-aggregation disease.
CONCLUSIONS: We provide diagnostic criteria for MiTES and improved longitudinal data. MiTES and CIP are distinct phenotypes, despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells. We hypothesize that the developmental environment of the trigeminal ganglion is unique and critically sensitive to pre- and postnatal levels of PRDM12.
Midfacial toddler excoriation syndrome (MiTES) causes facial itching and scratching in babies during their first year of life. MiTES tends to improve over the time period of approximately 10 years, but it can leave scars. Congenital insensitivity to pain (CIP) is a condition where a person cannot feel pain and is present from birth. This study looked at two conditions: MiTES and CIP. We specifically investigated changes in a gene called PRDM12, focusing on a part of the gene called the polyalanine tract – a sequence of many alanines (alanine is a type of amino acid). We discovered that the normal range for this sequence is between 7 and 15 alanines. If there are 16 to 18 alanines, it is associated with MiTES and causes the PRDM12 protein to clump together inside the cell. However, if there are 19 alanines, it leads to CIP, and the PRDM12 protein clumps together and moves to the cytoplasm, where it should not be. We found new evidence to suggest that MiTES is a disease where proteins clump together. Overall, our study findings show that despite there only being a small change in the same gene, MiTES and CIP are very different conditions.
OBJECTIVE: To assess the genotype and phenotype of nine new, nine atypical and six previously reported patients diagnosed with MiTES.
METHODS: Using cell lines with homozygous PR domain zinc finger protein 12 (PRDM12) containing 12 alanines (12A; normal), 18A (MiTES) and 19A (CIP), we examined PRDM12 aggregation and subcellular localization by image-separation confocal microscopy and subcellular fractionation Western blotting.
RESULTS: MiTES presents in the first year of life; in all cases the condition regresses over the first decade, leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12 CIP are rarely found. The genotype-phenotype study of the PRDM12 polyalanine tract shows that having 7-15 alanines is normal; 16-18 alanines is associated with MiTES; 19 alanines leads to CIP; and no clinically atypical cases of MiTES had a polyalanine tract expansion. PRDM12 aggregation and subcellular localization differed significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein-aggregation disease.
CONCLUSIONS: We provide diagnostic criteria for MiTES and improved longitudinal data. MiTES and CIP are distinct phenotypes, despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells. We hypothesize that the developmental environment of the trigeminal ganglion is unique and critically sensitive to pre- and postnatal levels of PRDM12.
Midfacial toddler excoriation syndrome (MiTES) causes facial itching and scratching in babies during their first year of life. MiTES tends to improve over the time period of approximately 10 years, but it can leave scars. Congenital insensitivity to pain (CIP) is a condition where a person cannot feel pain and is present from birth. This study looked at two conditions: MiTES and CIP. We specifically investigated changes in a gene called PRDM12, focusing on a part of the gene called the polyalanine tract – a sequence of many alanines (alanine is a type of amino acid). We discovered that the normal range for this sequence is between 7 and 15 alanines. If there are 16 to 18 alanines, it is associated with MiTES and causes the PRDM12 protein to clump together inside the cell. However, if there are 19 alanines, it leads to CIP, and the PRDM12 protein clumps together and moves to the cytoplasm, where it should not be. We found new evidence to suggest that MiTES is a disease where proteins clump together. Overall, our study findings show that despite there only being a small change in the same gene, MiTES and CIP are very different conditions.
摘要：
背景：PRDM12聚丙氨酸道扩张导致两种不同的疾病；面中蹒跚学步者阵痛综合征（MiTES）-瘙痒与纯合18丙氨酸相关的正常疼痛感觉（18A），和先天性疼痛不敏感（CIP）与纯合子19A正常瘙痒。了解表型，基因型，MiTES的发病机制不完全。为什么PRDM1218A与19A可以引起几乎相反的表型是未知的;没有其他聚丙氨酸或聚谷氨酰胺道扩张疾病引起两种这样的不同表型。
方法：我们评估了9个新的基因型和表型，9非典型的，和6例先前报告的诊断为MiTES的患者。使用具有12A纯合PRDM12的细胞系（正常），图18A(MiTES)和19A(CIP)我们通过图像分离共聚焦显微镜和亚细胞分级分离蛋白质印迹检查了PRDM12聚集和亚细胞定位。
结果：MiTES出现在生命的第一年，在所有情况下，这种情况在头十年都会消退，留下疤痕。MiTES表型是高度独特的。很少发现与PRDM12-CIP重叠的特征。PRDM12聚丙氨酸道的基因型-表型研究表明，7A-15A是正常的；16A-18A与MiTES相关；19A导致CIP；并且没有临床非典型MiTES病例有扩展。PRDM12聚集和亚细胞定位在18A和正常12A细胞系之间以及18A和19A细胞系之间显著不同。MiTES是一种新的蛋白质聚集疾病。
结论：我们提供了MiTES的诊断标准，和改进的纵向数据。MiTES和CIP是不同的表型，尽管它们的基因型在PRDM12聚丙氨酸束中随单个丙氨酸而变化。我们发现了正常细胞表型之间的明显区别，MiTES和CIP细胞。.我们假设三叉神经节的发育环境是独特的，并且对PRDM12的产前和产后水平非常敏感。
方法：我们评估了9个新的基因型和表型，9非典型的，和6例先前报告的诊断为MiTES的患者。使用具有12A纯合PRDM12的细胞系（正常），图18A(MiTES)和19A(CIP)我们通过图像分离共聚焦显微镜和亚细胞分级分离蛋白质印迹检查了PRDM12聚集和亚细胞定位。
结果：MiTES出现在生命的第一年，在所有情况下，这种情况在头十年都会消退，留下疤痕。MiTES表型是高度独特的。很少发现与PRDM12-CIP重叠的特征。PRDM12聚丙氨酸道的基因型-表型研究表明，7A-15A是正常的；16A-18A与MiTES相关；19A导致CIP；并且没有临床非典型MiTES病例有扩展。PRDM12聚集和亚细胞定位在18A和正常12A细胞系之间以及18A和19A细胞系之间显著不同。MiTES是一种新的蛋白质聚集疾病。
结论：我们提供了MiTES的诊断标准，和改进的纵向数据。MiTES和CIP是不同的表型，尽管它们的基因型在PRDM12聚丙氨酸束中随单个丙氨酸而变化。我们发现了正常细胞表型之间的明显区别，MiTES和CIP细胞。.我们假设三叉神经节的发育环境是独特的，并且对PRDM12的产前和产后水平非常敏感。
