Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1

Abstract

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.

Loss of PI3-kinase activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration and intestinal homeostasis

“…Inositol pentakisphosphate-2-kinase (IPPK) catalyzes the conversion of IP5 to IP6 3 . Multiple inositol polyphosphate phosphatase 1 (MINPP1) hydrolyzes IP5 and IP6 to IP3 15 (Figure 2 C). To examine the importance of IP5/6 in AKT Thr308 activation, we over-expressed MINPP1 in HEK293 cells, followed by stimulation with insulinlike growth factor 1 (IGF1) for 15 minutes.…”

Identification and functional characterization of multiple inositol polyphosphate phosphatase1 (Minpp1) isoform-2 in exosomes with potential to modulate tumor microenvironment

“…The ER stress-related apoptotic pathways have extensively been targeted in various diseases, including neurodegenerative disorders [ 72 ], cancer, type-2 diabetes [ 73 ], intestinal inflammation [ 74 ], amyotrophic sclerosis (ALS) [ 75 ], and many more. Some of these disorders such as neurodegenerative [ 76 , 77 ], single nucleotide polymorphisms (SNP) mutations that affect the milk fatty acids (FAs) traits in Chinese Holstein [ 78 ], a glycolytic bypass in Hepatitis-B virus (HBV) positive hepatocellular carcinoma (HCC) [ 79 ], differentiation and apoptosis [ 51 , 80 ] are implicated in involving Minpp1. Previous work from this group has reported a link between Minpp1 and ER stress [ 56 ].…”

Plasma proteome profiling combined with clinical and genetic features reveals the pathophysiological characteristics of β-thalassemia

“…Notably, this is the first report of elevated multiple inositol polyphosphate phosphatase 1 (MINPP1) in the plasma of patients with β-thalassemia. As elevated expression of MINPP1 involved in pontocerebellar hypoplasia ( Appelhof et al., 2020 ; Ucuncu et al., 2020 ), it may be a modulator of neurodegenerative syndrome in β-thalassemia.…”