TY - JOUR
T1 - Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1
AU - Appelhof, Bart
AU - Wagner, Matias
AU - Hoefele, Julia
AU - Heinze, Anja
AU - Roser, Timo
AU - Koch-Hogrebe, Margarete
AU - Roosendaal, Stefan D.
AU - Dehghani, Mohammadreza
AU - Mehrjardi, Mohammad Yahya Vahidi
AU - Torti, Erin
AU - Houlden, Henry
AU - Maroofian, Reza
AU - Rajabi, Farrah
AU - Sticht, Heinrich
AU - Baas, Frank
AU - Wieczorek, Dagmar
AU - Jamra, Rami Abou
N1 - Funding Information: Acknowledgements We thank the patients and the families for their contribution to this study. We like to thank Rolph Pfundt (Radbou-dumc, Nijmegen) for help with the conformation of the UPD of chromosome 10. We would like to thank Bernt Popp (Leipzig, Germany) for calculating the probabilities of autosomal recessive LoF in MINPP1. DW is member of ERN-ITHACA and the Zentrum für Seltene Erkrankungen Düsseldorf (ZSED). This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Publisher Copyright: © 2020, The Author(s).
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85095702884&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41431-020-00749-x
DO - https://doi.org/10.1038/s41431-020-00749-x
M3 - Article
C2 - 33168985
SN - 1018-4813
VL - 29
SP - 411
EP - 421
JO - European journal of human genetics
JF - European journal of human genetics
IS - 3
ER -