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Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1—further expansion of the phenotypic spectrum

Osteogenesis imperfecta (OI) is a heritable disorder of bone metabolism characterized by multiple fractures with minimal trauma. Autosomal recessive OI type VIII is associated with biallelic pathogenic variants in P3H1 and classically characterized by skeletal anomalies in addition to significant bo...

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Autores principales: Mikhail, Kristen A., VanSickle, Elizabeth, Rossetti, Linda Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10111797/
https://www.ncbi.nlm.nih.gov/pubmed/36963805
http://dx.doi.org/10.1101/mcs.a006260
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author Mikhail, Kristen A.
VanSickle, Elizabeth
Rossetti, Linda Z.
author_facet Mikhail, Kristen A.
VanSickle, Elizabeth
Rossetti, Linda Z.
author_sort Mikhail, Kristen A.
collection PubMed
description Osteogenesis imperfecta (OI) is a heritable disorder of bone metabolism characterized by multiple fractures with minimal trauma. Autosomal recessive OI type VIII is associated with biallelic pathogenic variants in P3H1 and classically characterized by skeletal anomalies in addition to significant bone fragility, sometimes presenting with in utero fractures and/or neonatal lethality. P3H1 encodes a collagen prolyl hydroxylase that critically 3-hydroxylates proline residue 986 on the α chain of collagen types I and II to achieve proper folding and assembly of mature collagen and is present in a complex with CRTAP and CypB. Most individuals with OI type VIII have had biallelic predicted loss-of-function variants leading to reduced or absent levels of P3H1 mRNA. The reported missense variants have all fallen in the catalytic domain of the protein and are thought to be associated with a milder phenotype. Here, we describe an infant presenting with five long bone fractures in the first year of life found to have a novel missense variant in trans with a nonsense variant in P3H1 without any other bony anomalies on imaging. We hypothesize that missense variants in the catalytic domain of P3H1 lead to decreased but not absent hydroxylation of Pro986, with preserved KDEL retention signal and complex stability, causing an attenuated phenotype.
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spelling pubmed-101117972023-04-19 Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1—further expansion of the phenotypic spectrum Mikhail, Kristen A. VanSickle, Elizabeth Rossetti, Linda Z. Cold Spring Harb Mol Case Stud Research Report Osteogenesis imperfecta (OI) is a heritable disorder of bone metabolism characterized by multiple fractures with minimal trauma. Autosomal recessive OI type VIII is associated with biallelic pathogenic variants in P3H1 and classically characterized by skeletal anomalies in addition to significant bone fragility, sometimes presenting with in utero fractures and/or neonatal lethality. P3H1 encodes a collagen prolyl hydroxylase that critically 3-hydroxylates proline residue 986 on the α chain of collagen types I and II to achieve proper folding and assembly of mature collagen and is present in a complex with CRTAP and CypB. Most individuals with OI type VIII have had biallelic predicted loss-of-function variants leading to reduced or absent levels of P3H1 mRNA. The reported missense variants have all fallen in the catalytic domain of the protein and are thought to be associated with a milder phenotype. Here, we describe an infant presenting with five long bone fractures in the first year of life found to have a novel missense variant in trans with a nonsense variant in P3H1 without any other bony anomalies on imaging. We hypothesize that missense variants in the catalytic domain of P3H1 lead to decreased but not absent hydroxylation of Pro986, with preserved KDEL retention signal and complex stability, causing an attenuated phenotype. Cold Spring Harbor Laboratory Press 2023-02 /pmc/articles/PMC10111797/ /pubmed/36963805 http://dx.doi.org/10.1101/mcs.a006260 Text en © 2023 Mikhail et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Mikhail, Kristen A.
VanSickle, Elizabeth
Rossetti, Linda Z.
Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1—further expansion of the phenotypic spectrum
title Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1—further expansion of the phenotypic spectrum
title_full Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1—further expansion of the phenotypic spectrum
title_fullStr Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1—further expansion of the phenotypic spectrum
title_full_unstemmed Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1—further expansion of the phenotypic spectrum
title_short Milder presentation of osteogenesis imperfecta type VIII due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in P3H1—further expansion of the phenotypic spectrum
title_sort milder presentation of osteogenesis imperfecta type viii due to compound heterozygosity for a predicted loss-of-function variant and novel missense variant in p3h1—further expansion of the phenotypic spectrum
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10111797/
https://www.ncbi.nlm.nih.gov/pubmed/36963805
http://dx.doi.org/10.1101/mcs.a006260
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