Pontocerebellar hypoplasia (PCH) describes a group of rare heterogeneous neurodegenerative diseases with prenatal onset. Here we describe eight children with PCH from four unrelated families harboring the homozygous MINPP1 (NM_004897.4) variants; c.75_94del, p.(Leu27Argfs*39), c.851 C > A, p.(Ala284Asp), c.1210 C > T, p.(Arg404*), and c.992 T > G, p.(Ile331Ser). The homozygous p.(Leu27Argfs*39) change is predicted to result in a complete absence of MINPP1. The p.(Arg404*) would likely lead to a nonsense mediated decay, or alternatively, a loss of several secondary structure elements impairing protein folding. The missense p.(Ala284Asp) affects a buried, hydrophobic residue within the globular domain. The introduction of aspartic acid is energetically highly unfavorable and therefore predicted to cause a significant reduction in protein stability. The missense p.(Ile331Ser) affects the tight hydrophobic interactions of the isoleucine by the disruption of the polar side chain of serine, destabilizing the structure of MINPP1. The overlap of the above-mentioned genotypes and phenotypes is highly improbable by chance. MINPP1 is the only enzyme that hydrolyses inositol phosphates in the endoplasmic reticulum lumen and several studies support its role in stress induced apoptosis. The pathomechanism explaining the disease mechanism remains unknown, however several others genes of the inositol phosphatase metabolism (e.g., INPP5K, FIG4, INPP5E, ITPR1) are correlated with phenotypes of neurodevelopmental disorders. Taken together, we present MINPP1 as a novel autosomal recessive pontocerebellar hypoplasia gene.

脑桥小脑发育不全（PCH）描述了一组罕见的异质性神经退行性疾病，产前发病。在这里，我们描述了来自四个不相关家庭的八名 PCH 儿童，他们携带纯合子MINPP1(NM_004897.4) 变体；c.75_94del, p.(Leu27Argfs*39), c.851 C > A, p.(Ala284Asp), c.1210 C > T, p.(Arg404*), 和 c.992 T > G, p.( Ile331Ser)。预计纯合 p.(Leu27Argfs*39) 变化将导致 MINPP1 完全缺失。p.(Arg404*) 可能会导致无意义介导的衰变，或者，一些二级结构元素的损失会损害蛋白质折叠。错义 p.(Ala284Asp) 影响球状结构域内的埋藏疏水残基。天冬氨酸的引入在能量上非常不利，因此预计会导致蛋白质稳定性显着降低。错义 p.(Ile331Ser) 通过破坏丝氨酸的极性侧链来影响异亮氨酸的紧密疏水相互作用，从而破坏 MINPP1 的结构。上述基因型和表型的重叠是非常不可能偶然发生的。MINPP1 是唯一在内质网腔内水解肌醇磷酸盐的酶，一些研究支持其在应激诱导的细胞凋亡中的作用。解释疾病机制的病理机制仍然未知，但是肌醇磷酸酶代谢的其他几个基因（例如，INPP5K、FIG4、INPP5E、ITPR1）与神经发育障碍的表型相关。总之，我们将MINPP1 呈现为一种新的常染色体隐性遗传的脑桥小脑发育不全基因。