Appelhof, B;
Wagner, M;
Hoefele, J;
Heinze, A;
Roser, T;
Koch-Hogrebe, M;
Roosendaal, SD;
Dehghani, M;
Mehrjardi, MYV;
Torti, E;
et al.
Appelhof, B; Wagner, M; Hoefele, J; Heinze, A; Roser, T; Koch-Hogrebe, M; Roosendaal, SD; Dehghani, M; Mehrjardi, MYV; Torti, E; Houlden, H; Maroofian, R; Rajabi, F; Sticht, H; Baas, F; Wieczorek, D; Jamra, RA
(2021)
Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1.
Eur J Hum Genet, 29 (3).
pp. 411-421.
ISSN 1476-5438
https://doi.org/10.1038/s41431-020-00749-x
SGUL Authors: Maroofian, Reza
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.
Item Type: |
Article
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Additional Information: |
© The Author(s) 2020. This article is published with open access
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: |
0604 Genetics, Genetics & Heredity |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Eur J Hum Genet |
ISSN: |
1476-5438 |
Language: |
eng |
Dates: |
Date | Event |
---|
9 November 2020 | Published Online | March 2021 | Published | 22 September 2020 | Accepted |
|
Publisher License: |
Creative Commons: Attribution 4.0 |
PubMed ID: |
33168985 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/112613 |
Publisher's version: |
https://doi.org/10.1038/s41431-020-00749-x |
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