乙基亚硝基脲诱导的PHEX基因点突变导致外显子跳跃、X连锁低磷血症和佝偻病。
An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets.
作者信息
Carpinelli Marina R, Wicks Ian P, Sims Natalie A, O'Donnell Kristy, Hanzinikolas Katherine, Burt Rachel, Foote Simon J, Bahlo Melanie, Alexander Warren S, Hilton Douglas J
机构信息
Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Victoria, Australia.
出版信息
Am J Pathol. 2002 Nov;161(5):1925-33. doi: 10.1016/S0002-9440(10)64468-9.
Abstract
We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.
摘要
我们描述了一只小鼠的临床、遗传、生化和分子特征，该小鼠出现在用化学诱变剂乙基硝基脲进行的随机诱变筛选的第一代（G(1)）中。观察到该小鼠具有以X连锁显性遗传模式遗传的骨骼异常。致病突变被命名为骨骼异常1（Ska1），它被证明是位于X染色体上的与内肽酶具有同源性的磷酸盐调节基因（Phex）第8外显子之后的剪接供体位点的单碱基对突变。这个点突变导致Phex mRNA跳过第8外显子，引起低磷血症和佝偻病特征。这种实验诱导的表型反映了人类的X连锁低磷血症；直接证实了Phex在磷酸盐稳态、正常骨骼发育和佝偻病中的作用；并说明了诱变在探索人类疾病动物模型方面的作用。
相似文献
1
An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets.乙基亚硝基脲诱导的PHEX基因点突变导致外显子跳跃、X连锁低磷血症和佝偻病。
Am J Pathol. 2002 Nov;161(5):1925-33. doi: 10.1016/S0002-9440(10)64468-9.
2
A novel Phex mutation in a new mouse model of hypophosphatemic rickets.新型 Phex 突变导致新型低血磷性佝偻病小鼠模型发病。
J Cell Biochem. 2012 Jul;113(7):2432-41. doi: 10.1002/jcb.24115.
3
Whole Exome Sequencing Reveals Novel PHEX Splice Site Mutations in Patients with Hypophosphatemic Rickets.全外显子组测序揭示低磷性佝偻病患者中新型PHEX剪接位点突变
PLoS One. 2015 Jun 24;10(6):e0130729. doi: 10.1371/journal.pone.0130729. eCollection 2015.
4
New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice.Phex基因中的新型基因内缺失阐明了小鼠中与X连锁低磷血症相关的异常情况。
Mamm Genome. 2004 Mar;15(3):151-61. doi: 10.1007/s00335-003-2310-z.
5
A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice.一种具有糖基化缺陷的新型Phex突变导致小鼠低磷血症和佝偻病。
J Biomed Sci. 2008 Jan;15(1):47-59. doi: 10.1007/s11373-007-9199-6. Epub 2007 Aug 21.
6
A PHEX gene mutation is responsible for adult-onset vitamin D-resistant hypophosphatemic osteomalacia: evidence that the disorder is not a distinct entity from X-linked hypophosphatemic rickets.PHEX基因突变是成人期维生素D抵抗性低磷性骨软化症的病因：该疾病并非与X连锁低磷性佝偻病不同的独立疾病的证据。
J Clin Endocrinol Metab. 1998 Oct;83(10):3459-62. doi: 10.1210/jcem.83.10.5167.
7
Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice.成纤维细胞生长因子-23的纯合性缺失导致高磷血症和骨骼生成受损，并可逆转Phex基因缺陷小鼠的低磷血症。
Matrix Biol. 2004 Nov;23(7):421-32. doi: 10.1016/j.matbio.2004.09.007.
8
A mosaic mutation of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) in X-linked hypophosphatemic rickets with mild bone phenotypes.X 连锁低磷血症性佝偻病伴轻微骨骼表型中具有 X 染色体内肽酶同源性的磷酸调节基因镶嵌突变（PHEX）。
Endocr J. 2021 Sep 28;68(9):1135-1141. doi: 10.1507/endocrj.EJ20-0809. Epub 2021 Apr 28.
9
Overexpression of human PHEX under the human beta-actin promoter does not fully rescue the Hyp mouse phenotype.在人β-肌动蛋白启动子调控下的人PHEX过表达并不能完全挽救Hyp小鼠的表型。
J Bone Miner Res. 2005 Jul;20(7):1149-60. doi: 10.1359/JBMR.050212. Epub 2005 Feb 21.
10
A New Mosaic Mutation of PHEX Gene: A Case Report of a Boy with Hypophosphatemic Rickets.一种新的 PHEX 基因突变：一名男性低磷血症性佝偻病患儿的病例报告。
Endocr Metab Immune Disord Drug Targets. 2023;23(9):1235-1239. doi: 10.2174/1871530323666230227142202.
引用本文的文献
1
PHEX Mutation Increases Expression in a New ENU Mouse Model for XLH Disease.PHEX 突变增加了 XLH 疾病新 ENU 小鼠模型中的表达。
Genes (Basel). 2022 Jul 28;13(8):1356. doi: 10.3390/genes13081356.
2
Novel PHEX gene locus-specific database: Comprehensive characterization of vast number of variants associated with X-linked hypophosphatemia (XLH).新型 PHEX 基因座特异性数据库：对大量与 X 连锁低磷血症 (XLH) 相关的变异体进行全面特征描述。
Hum Mutat. 2022 Feb;43(2):143-157. doi: 10.1002/humu.24296. Epub 2021 Dec 5.
3
FGF23 and its role in X-linked hypophosphatemia-related morbidity.成纤维细胞生长因子 23 及其在 X 连锁低磷血症相关发病机制中的作用。
Orphanet J Rare Dis. 2019 Feb 26;14(1):58. doi: 10.1186/s13023-019-1014-8.
4
Dosage effect of a Phex mutation in a murine model of X-linked hypophosphatemia.X 连锁低磷血症小鼠模型中 Phex 突变的剂量效应。
Calcif Tissue Int. 2013 Aug;93(2):155-62. doi: 10.1007/s00223-013-9736-4. Epub 2013 May 23.
5
New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis.基于全基因组ENU 诱变的代谢性骨疾病新小鼠模型。
Mamm Genome. 2012 Aug;23(7-8):416-30. doi: 10.1007/s00335-012-9397-z. Epub 2012 Apr 21.
6
A Phex mutation in a murine model of X-linked hypophosphatemia alters phosphate responsiveness of bone cells.X 连锁低磷血症的鼠模型中的 Phex 突变改变了骨细胞对磷酸盐的反应性。
J Bone Miner Res. 2012 Feb;27(2):453-60. doi: 10.1002/jbmr.544.
7
Kbus/Idr, a mutant mouse strain with skeletal abnormalities and hypophosphatemia: identification as an allele of 'Hyp'.Kbus/Idr，一种具有骨骼异常和低血磷症的突变鼠品系：鉴定为“Hyp”的等位基因。
J Biomed Sci. 2011 Aug 20;18(1):60. doi: 10.1186/1423-0127-18-60.
8
N-ethyl-N-nitrosourea mutagenesis produced a small number of mice with altered plasma electrolyte levels.N-乙基-N-亚硝基脲诱变产生了少量血浆电解质水平改变的小鼠。
J Biomed Sci. 2009 Jun 8;16(1):53. doi: 10.1186/1423-0127-16-53.
9
Role of matrix extracellular phosphoglycoprotein in the pathogenesis of X-linked hypophosphatemia.基质细胞外磷酸糖蛋白在X连锁低磷血症发病机制中的作用。
J Am Soc Nephrol. 2005 Jun;16(6):1645-53. doi: 10.1681/ASN.2004121060. Epub 2005 Apr 20.
10
New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice.Phex基因中的新型基因内缺失阐明了小鼠中与X连锁低磷血症相关的异常情况。
Mamm Genome. 2004 Mar;15(3):151-61. doi: 10.1007/s00335-003-2310-z.
本文引用的文献
1
Hypophosphatemic rickets.低磷性佝偻病
Rev Endocr Metab Disord. 2001 Apr;2(2):165-73. doi: 10.1023/a:1010054727323.
2
FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate.成纤维细胞生长因子-23抑制肾小管磷酸盐转运，且是磷酸盐调节内肽酶同源性X连锁基因（PHEX）的底物。
Biochem Biophys Res Commun. 2001 Jun 22;284(4):977-81. doi: 10.1006/bbrc.2001.5084.
3
Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.成纤维细胞生长因子23作为肿瘤诱导性骨软化症致病因素的克隆与鉴定
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6500-5. doi: 10.1073/pnas.101545198. Epub 2001 May 8.
4
Bone homeostasis in growth hormone receptor-null mice is restored by IGF-I but independent of Stat5.生长激素受体缺失小鼠的骨稳态可通过胰岛素样生长因子-I恢复，但与信号转导和转录激活因子5无关。
J Clin Invest. 2000 Nov;106(9):1095-103. doi: 10.1172/JCI10753.
5
Developmental expression and tissue distribution of Phex protein: effect of the Hyp mutation and relationship to bone markers.Phex蛋白的发育表达及组织分布：Hyp突变的影响及其与骨标志物的关系
J Bone Miner Res. 2000 Aug;15(8):1440-50. doi: 10.1359/jbmr.2000.15.8.1440.
6
Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues.
Eur J Hum Genet. 1999 Jul;7(5):615-9. doi: 10.1038/sj.ejhg.5200341.
7
Mutational analysis of PHEX gene in X-linked hypophosphatemia.X连锁低磷血症中PHEX基因的突变分析。
J Clin Endocrinol Metab. 1998 Oct;83(10):3615-23. doi: 10.1210/jcem.83.10.5180.
8
Partial deletion of both the spermine synthase gene and the Pex gene in the X-linked hypophosphatemic, gyro (Gy) mouse.X连锁低磷血症“陀螺”（Gy）小鼠中精胺合酶基因和Pex基因的部分缺失。
Genomics. 1998 Mar 15;48(3):289-95. doi: 10.1006/geno.1997.5169.
9
Pex mRNA is localized in developing mouse osteoblasts and odontoblasts.Pex信使核糖核酸定位于发育中的小鼠成骨细胞和成牙本质细胞中。
J Histochem Cytochem. 1998 Apr;46(4):459-68. doi: 10.1177/002215549804600405.
10
Using targeted large deletions and high-efficiency N-ethyl-N-nitrosourea mutagenesis for functional analyses of the mammalian genome.利用靶向大片段缺失和高效N-乙基-N-亚硝基脲诱变技术对哺乳动物基因组进行功能分析。
Methods. 1997 Dec;13(4):423-36. doi: 10.1006/meth.1997.0548.
Zotero 插件