Language
English
Publication Date
5-29-2025
Journal
International Journal of Molecular Sciences
DOI
10.3390/ijms26115213
PMID
40508022
PMCID
PMC12154299
PubMedCentral® Full Text Version
Post-print
Abstract
Pontocerebellar hypoplasia (PCH) encompasses a group of autosomal recessive neurodegenerative disorders marked by cerebellar and pontine atrophy. Multiple subtypes of PCH have been identified, among which the rare subtype PCH type 16 is caused by MINPP1 genetic variants. MINPPI encodes an enzyme essential for inositol polyphosphate dephosphorylation, regulating calcium and iron homeostasis. We conducted genome sequencing on a proband from the consanguineous family, who presented with a severe neurodegenerative disorder, to identify the underlying cause of disease. A comprehensive clinical assessment in addition to neuroradiological findings are described. We performed the functional validation of the identified variant and conducted untargeted metabolomic analyses. The clinical and radiological assessment of the patient showed a congenital brain anomaly and neurodegenerative symptoms. Further genetic analysis identified a homozygous loss-of-function variant (c.1401del, p.Ser468Valfs10*) in MINPP1, providing molecular confirmation of a clinical PCH diagnosis. While real-time quantitative PCR (RT-qPCR) showed that MINPP1 gene expression was unaffected in the proband, Western blot analysis demonstrated reduced protein abundance, supporting a pathogenic role of the variant. Metabolomic profiling revealed elevated lipid levels and disrupted inositol metabolism, providing further insights into the disease mechanism. These findings establish the pathogenicity of the p.Ser468Valfs10* variant in MINPP1 and highlight inositol metabolism as a potential pathway involved in PCH16, advancing the understanding of the pathophysiology of the disease.
Keywords
Humans, Alleles, Cerebellar Diseases, Loss of Function Mutation, Neurodevelopmental Disorders, Pedigree, Phosphoric Monoester Hydrolases, pontocerebellar hypoplasia, neurodegenerative disorder, Middle East, rare disease, whole genome sequencing
Published Open-Access
yes
Recommended Citation
Al-Maraghi, Aljazi; Shaath, Rulan; Ford, Katherine; et al., "Biallelic Loss-of-Function Variant in MINPP1 Causes Pontocerebellar Hypoplasia with Characteristic Severe Neurodevelopmental Disorder" (2025). Faculty and Staff Publications. 5167.
https://digitalcommons.library.tmc.edu/baylor_docs/5167
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