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.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2023-02-01 DOI:10.1101/mcs.a006260
Kristen A Mikhail, Elizabeth VanSickle, Linda Z Rossetti
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Abstract

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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由于p3h1中预测的功能缺失变异和新型错义变异的复合杂合性,出现了较轻的成骨不完善型VIII -进一步扩大了表型谱。
成骨不全症(OI)是一种遗传性骨代谢疾病,其特征是多发骨折且创伤较小。常染色体隐性VIII型成骨不全与P3H1的双等位基因致病变异有关,其典型特征是骨骼异常和明显的骨骼脆性,有时表现为子宫内骨折和/或新生儿死亡。P3H1编码一种胶原脯氨酸羟化酶,该酶对I型和II型胶原α链上的脯氨酸残基986进行3-羟化,以实现成熟胶原的适当折叠和组装,并与CRTAP和CypB复合物存在。大多数VIII型成骨不全患者具有双等位基因预测的功能丧失变异,导致P3H1 mRNA水平降低或缺失。报道的错义变体都落在蛋白质的催化区域,并且被认为与较温和的表型有关。在这里,我们描述了一名婴儿,在生命的第一年出现了五次长骨骨折,发现在trans中有一种新的错义变异,在P3H1中有一种无义变异,而在影像学上没有任何其他骨异常。我们假设P3H1催化结构域的错义变异导致Pro986羟基化减少但不是没有,保留了KDEL保留信号和复合物的稳定性,导致表型减弱。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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