Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174^*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

中文翻译：

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NMIHBA 由缺乏短链外多磷酸酶活性的亚形性 PRUNE1 变体引起


伴有小头畸形、张力减退和可变性脑异常的神经发育障碍 (NMIHBA) 是一种常染色体隐性遗传神经发育和神经退行性疾病，其特征是整体发育迟缓和严重智力障碍。小头畸形、进行性皮质萎缩、小脑发育不全和髓鞘形成延迟是受影响个体的神经学特征。 NMIHBA 是由编码李子外多磷酸酶 1 的PRUNE1中的双等位基因变异引起的。我们提供了两个受影响的兄弟姐妹的深入临床描述，这些兄弟姐妹携带复合杂合变异等位基因，c.383G > A (p.Arg128Gln)、c.520G > T (p .Gly174 ^* ) 在PRUNE1中。为了深入了解疾病生物学，我们对保守的 N 末端天冬氨酸-组氨酸-组氨酸 (DHH) 基序内的错义变异进行了生化表征，并提供证据证明它们会导致蛋白质结构不稳定和/或外切多磷酸酶活性丧失。 Prune1的基因消除会导致小鼠妊娠中期死亡，这与胚胎生长和血管发育的干扰有关。我们的研究结果表明，NMIHBA 由人类亚等位基因变异引起，并强调了 PRUNE1 外多磷酸酶活性在神经发育中的潜在关键作用。