An N-Ethyl-N-Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion

Christopher T Esapa, Sian E Piret, M. Andrew Nesbit, Gethin Thomas, Leslie Coulton, Saumya Kumar, Ann-Marie Mallon, Ilaria Bellatuono, Matthew Brown, Peter Croucher, Paul Potter, Steve DM Brown, Roger D Cox, Rajesh V. Thakker

Research output: Contribution to journalArticle

Abstract

Kyphosis and scoliosis are common spinal disorders that occur as part of complex syndromes or as nonsyndromic, idiopathic diseases. Familial and twin studies implicate genetic involvement, although the causative genes for idiopathic kyphoscoliosis remain to be identified. To facilitate these studies, we investigated progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) and assessed them for morphological and radiographic abnormalities. This identified a mouse with kyphoscoliosis due to fused lumbar vertebrae, which was inherited as an autosomal dominant trait; the phenotype was designated as hereditary vertebral fusion (HVF) and the locus as Hvf. Micro-computed tomography (μCT) analysis confirmed the occurrence of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae in HVF mice, consistent with a pattern of blocked vertebrae due to failure of segmentation. μCT scans also showed the lumbar vertebral column of HVF mice to have generalized disc narrowing, displacement with compression of the neural spine, and distorted transverse processes. Histology of lumbar vertebrae revealed HVF mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centers. Genetic mapping using a panel of single nucleotide polymorphic (SNP) loci arranged in chromosome sets and DNA samples from 23 HVF (eight males and 15 females) mice, localized Hvf to chromosome 4A3 and within a 5-megabase (Mb) region containing nine protein coding genes, two processed transcripts, three microRNAs, five small nuclear RNAs, three large intergenic noncoding RNAs, and 24 pseudogenes. However, genome sequence analysis in this interval did not identify any abnormalities in the coding exons, or exon-intron boundaries of any of these genes. Thus, our studies have established a mouse model for a monogenic form of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae, and further identification of the underlying genetic defect will help elucidate the molecular mechanisms involved in kyphoscoliosis.
LanguageEnglish
Pages154-163
JournalJBMR Plus
Volume2
Issue number3
Publication statusPublished - 8 Mar 2018

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Ethylnitrosourea
Lumbar Vertebrae
Pseudogenes
Spine
Exons
Chromosomes
Small Nuclear RNA
Intervertebral Disc Displacement
Untranslated RNA
Kyphosis
Twin Studies
Mutagens
Scoliosis
MicroRNAs
Osteogenesis
Introns
Genes
Sequence Analysis
Histology
Nucleotides

Keywords

  • GENETIC ANIMAL MODELS; DISEASES AND DISORDERS OF/RELATED TO BONE; DXA; PRECLINICAL STUDIES; BONE QCT/MCT

Cite this

Esapa, C. T., Piret, S. E., Nesbit, M. A., Thomas, G., Coulton, L., Kumar, S., ... Thakker, R. V. (2018). An N-Ethyl-N-Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion. JBMR Plus, 2(3), 154-163.
Esapa, Christopher T ; Piret, Sian E ; Nesbit, M. Andrew ; Thomas, Gethin ; Coulton, Leslie ; Kumar, Saumya ; Mallon, Ann-Marie ; Bellatuono, Ilaria ; Brown, Matthew ; Croucher, Peter ; Potter, Paul ; Brown, Steve DM ; Cox, Roger D ; Thakker, Rajesh V. / An N-Ethyl-N-Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion. In: JBMR Plus. 2018 ; Vol. 2, No. 3. pp. 154-163.
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Esapa, CT, Piret, SE, Nesbit, MA, Thomas, G, Coulton, L, Kumar, S, Mallon, A-M, Bellatuono, I, Brown, M, Croucher, P, Potter, P, Brown, SDM, Cox, RD & Thakker, RV 2018, 'An N-Ethyl-N-Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion', JBMR Plus, vol. 2, no. 3, pp. 154-163.

An N-Ethyl-N-Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion. / Esapa, Christopher T; Piret, Sian E; Nesbit, M. Andrew; Thomas, Gethin; Coulton, Leslie; Kumar, Saumya; Mallon, Ann-Marie; Bellatuono, Ilaria; Brown, Matthew; Croucher, Peter; Potter, Paul; Brown, Steve DM; Cox, Roger D; Thakker, Rajesh V.

In: JBMR Plus, Vol. 2, No. 3, 08.03.2018, p. 154-163.

Research output: Contribution to journalArticle

TY - JOUR

T1 - An N-Ethyl-N-Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion

AU - Esapa, Christopher T

AU - Piret, Sian E

AU - Nesbit, M. Andrew

AU - Thomas, Gethin

AU - Coulton, Leslie

AU - Kumar, Saumya

AU - Mallon, Ann-Marie

AU - Bellatuono, Ilaria

AU - Brown, Matthew

AU - Croucher, Peter

AU - Potter, Paul

AU - Brown, Steve DM

AU - Cox, Roger D

AU - Thakker, Rajesh V.

PY - 2018/3/8

Y1 - 2018/3/8

N2 - Kyphosis and scoliosis are common spinal disorders that occur as part of complex syndromes or as nonsyndromic, idiopathic diseases. Familial and twin studies implicate genetic involvement, although the causative genes for idiopathic kyphoscoliosis remain to be identified. To facilitate these studies, we investigated progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) and assessed them for morphological and radiographic abnormalities. This identified a mouse with kyphoscoliosis due to fused lumbar vertebrae, which was inherited as an autosomal dominant trait; the phenotype was designated as hereditary vertebral fusion (HVF) and the locus as Hvf. Micro-computed tomography (μCT) analysis confirmed the occurrence of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae in HVF mice, consistent with a pattern of blocked vertebrae due to failure of segmentation. μCT scans also showed the lumbar vertebral column of HVF mice to have generalized disc narrowing, displacement with compression of the neural spine, and distorted transverse processes. Histology of lumbar vertebrae revealed HVF mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centers. Genetic mapping using a panel of single nucleotide polymorphic (SNP) loci arranged in chromosome sets and DNA samples from 23 HVF (eight males and 15 females) mice, localized Hvf to chromosome 4A3 and within a 5-megabase (Mb) region containing nine protein coding genes, two processed transcripts, three microRNAs, five small nuclear RNAs, three large intergenic noncoding RNAs, and 24 pseudogenes. However, genome sequence analysis in this interval did not identify any abnormalities in the coding exons, or exon-intron boundaries of any of these genes. Thus, our studies have established a mouse model for a monogenic form of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae, and further identification of the underlying genetic defect will help elucidate the molecular mechanisms involved in kyphoscoliosis.

AB - Kyphosis and scoliosis are common spinal disorders that occur as part of complex syndromes or as nonsyndromic, idiopathic diseases. Familial and twin studies implicate genetic involvement, although the causative genes for idiopathic kyphoscoliosis remain to be identified. To facilitate these studies, we investigated progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) and assessed them for morphological and radiographic abnormalities. This identified a mouse with kyphoscoliosis due to fused lumbar vertebrae, which was inherited as an autosomal dominant trait; the phenotype was designated as hereditary vertebral fusion (HVF) and the locus as Hvf. Micro-computed tomography (μCT) analysis confirmed the occurrence of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae in HVF mice, consistent with a pattern of blocked vertebrae due to failure of segmentation. μCT scans also showed the lumbar vertebral column of HVF mice to have generalized disc narrowing, displacement with compression of the neural spine, and distorted transverse processes. Histology of lumbar vertebrae revealed HVF mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centers. Genetic mapping using a panel of single nucleotide polymorphic (SNP) loci arranged in chromosome sets and DNA samples from 23 HVF (eight males and 15 females) mice, localized Hvf to chromosome 4A3 and within a 5-megabase (Mb) region containing nine protein coding genes, two processed transcripts, three microRNAs, five small nuclear RNAs, three large intergenic noncoding RNAs, and 24 pseudogenes. However, genome sequence analysis in this interval did not identify any abnormalities in the coding exons, or exon-intron boundaries of any of these genes. Thus, our studies have established a mouse model for a monogenic form of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae, and further identification of the underlying genetic defect will help elucidate the molecular mechanisms involved in kyphoscoliosis.

KW - GENETIC ANIMAL MODELS; DISEASES AND DISORDERS OF/RELATED TO BONE; DXA; PRECLINICAL STUDIES; BONE QCT/MCT

M3 - Article

VL - 2

SP - 154

EP - 163

JO - Journal of Bone and Mineral Research

T2 - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 3

ER -