Kokotović Tomislav, Langeslag Michiel, Lenartowicz Ewelina M, Manion John, Fell Christopher W, Alehabib Elham, Tafakhori Abbas, Darvish Hossein, Bellefroid Eric J, Neely G Gregory, Kress Michaela, Penninger Josef M, Nagy Vanja
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Front Mol Neurosci. 2021 Sep 27;14:720973. doi: 10.3389/fnmol.2021.720973. eCollection 2021.
PR domain-containing member 12 (PRDM12) is a key developmental transcription factor in sensory neuronal specification and survival. Patients with rare deleterious variants in are born with congenital insensitivity to pain (CIP) due to the complete absence of a subtype of peripheral neurons that detect pain. In this paper, we report two additional CIP cases with a novel homozygous variant. To elucidate the function of PRDM12 during mammalian development and adulthood, we generated temporal and spatial conditional mouse models. We find that PRDM12 is expressed throughout the adult nervous system. We observed that loss of PRDM12 during mid-sensory neurogenesis but not in the adult leads to reduced survival. Comparing cellular biophysical nociceptive properties in developmental and adult-onset PRDM12 deletion mouse models, we find that PRDM12 is necessary for proper nociceptive responses throughout life. However, we find that PRDM12 regulates distinct age-dependent transcriptional programs. Together, our results implicate PRDM12 as a viable therapeutic target for specific pain therapies even in adults.
含PR结构域蛋白12（PRDM12）是感觉神经元特化和存活过程中的关键发育转录因子。携带PRDM12罕见有害变异的患者由于完全缺乏检测疼痛的外周神经元亚型，出生时即患有先天性无痛觉（CIP）。在本文中，我们报告了另外两例携带新型纯合PRDM12变异的CIP病例。为了阐明PRDM12在哺乳动物发育和成年期的功能，我们构建了时空条件性小鼠模型。我们发现PRDM12在整个成年神经系统中均有表达。我们观察到，在感觉神经发生中期而非成年期缺失PRDM12会导致存活率降低。比较发育性和成年期PRDM12缺失小鼠模型中的细胞生物物理伤害感受特性，我们发现PRDM12在整个生命过程中对于适当的伤害感受反应都是必需的。然而，我们发现PRDM12调节不同的年龄依赖性转录程序。总之，我们的结果表明PRDM12即使在成年人中也是特定疼痛治疗的可行治疗靶点。
