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Appelhof, B.* ; Wagner, M. ; Hoefele, J.* ; Heinze, A.* ; Roser, T.* ; Koch-Hogrebe, M.* ; Roosendaal, S.D.* ; Dehghani, M.* ; Mehrjardi, M.Y.V.* ; Torti, E.* ; Houlden, H.* ; Maroofian, R.* ; Rajabi, F.* ; Sticht, H.* ; Baas, F.* ; Wieczorek, D.* ; Jamra, R.A.*

Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1.

Eur. J. Hum. Genet. 29, 411–421 (2020)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Inositol Polyphosphate Phosphatase; Mutations; Dystrophy; Atrophy; Links
ISSN (print) / ISBN 1018-4813
e-ISSN 1476-5438
Zeitschrift European Journal of Human Genetics
Quellenangaben Band: 29, Heft: , Seiten: 411–421 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen National Institute for Health Research University College London Hospitals Biomedical Research Centre