Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1

Eur J Hum Genet. 2021 Mar;29(3):411-421. doi: 10.1038/s41431-020-00749-x.

Bart Appelhof ¹, Matias Wagner ² ³, Julia Hoefele ³, Anja Heinze ⁴, Timo Roser ⁵, Margarete Koch-Hogrebe ⁶, Stefan D Roosendaal ⁷, Mohammadreza Dehghani ⁸, Mohammad Yahya Vahidi Mehrjardi ⁸, Erin Torti ⁹, Henry Houlden ¹⁰, Reza Maroofian ¹⁰, Farrah Rajabi ¹¹, Heinrich Sticht ¹², Frank Baas ¹³, Dagmar Wieczorek ¹⁴, Rami Abou Jamra ¹⁵

Affiliations

1 Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
2 Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany, Technical University of Munich, Munich, Germany.
3 Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
4 Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.
5 Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Haunersches Children's Hospital, Ludwig-Maximilian-University of Munich, Munich, Germany.
6 Vestische Kinder- und Jugendklinik, Datteln, Germany.
7 Department of Radiology, Amsterdam University Medical Centers, Amsterdam, Netherlands.
8 Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
9 GeneDx, Gaithersburg, USA.
10 Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.
11 Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachussetts, USA.
12 Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander -Nürnberg, Erlangen, Germany.
13 Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands. F.Baas@lumc.nl.
14 Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
15 Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany. rami.aboujamra@medizin.uni-leipzig.de.

PMID: 33168985 DOI: 10.1038/s41431-020-00749-x

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.

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