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Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with normal stature by whole exome sequencing; the tallest man had a height of 211 cm. Six heterozygous gene variants predicted as damaging were shared among the four genetically related tall individuals and not present in a family member with normal height. To gain insight into the putative role of these candidate genes in bone growth, we assessed the transcriptome of murine growth plate by microarray and RNA Seq. Two (Ift140, Nav2) of the six genes were well-expressed in the growth plate. Nav2 (p-value 1.91E-62) as well as Ift140 (p-value of 2.98E-06) showed significant downregulation of gene expression between the proliferative and hypertrophic zone, suggesting that these genes may be involved in the regulation of chondrocyte proliferation and/or hypertrophic differentiation. IFT140, NAV2 and SCAF11 have also significantly associated with height in GWAS studies. Pathway and network analysis indicated functional connections between IFT140, NAV2 and SCAF11 and previously associated (tall) stature genes. Knockout of the all-trans retinoic acid responsive gene, neuron navigator 2 NAV2, in Xenopus supports its functional role as a growth promotor. Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype.
Figure 1 Pedigree and height data. (A) Pedigree of family: Black symbols indicate individuals with tall stature. Individual I.2 is considered as borderline tall stature (grey symbol). White symbols indicate normal stature. Exome sequencing was carried out on DNA from individuals I.1, II.1, II.4 and III.1. DNA was also available from I.2, II.2 and III.2 but not for exome sequencing; no DNA was available from individual II.3 (declined). (B) Data on height and year of birth of Family A Height data were adjusted for secular trend and shrinking. SDS, Standard deviation score.
Figure 2 Ingenuity (IPA) Network analysis. The newly identified genes were used to show functional connections in context of known protein networks, based on data from the literature. No connections to known proteins could be established for CNGB1.
Figure 3 CRISPR/Cas-mediated knockout of nav2 causes enhanced embryonic growth. (A, B) Tadpole total body length measurements of three independent experiments. All experiments revealed a slightly increased average body size in nav2 sgRNA-injected specimens as compared to control littermates. (A) Three single experiments with sgRNA1 that specifically targets an exon orthologous to the exon harboring the human NAV2 missense mutation p.R2201C (exp.1, n=38 animals, stage 45; exp.2, n=102 animals, stage 44; exp.3, n=18 animals, stage 45); (B) Combined data of the three experiments in (A) after normalization to the mean of their controls revealed a significant increase of relative body sizes after sgRNA1 injections (p-value=0.023). Boxplot whiskers (error bars) are 1.5 * IQR +Q3 (upper), or 1.5 * IQR -Q1 (lower). co, control; exp., experiment; sgRNA, single-guide RNA; mm, millimeter.
Supplementary Figure 1 | Ingenuity (IPA) Network analysis. Known genes from the literature (n=86; in green colour) underlying tall stature were analysed using the IPA network analysis. The newly identified genes were added to predict functional connections in the context of known protein networks.
Supplementary Figure 2 | nav2 sgRNA2 causes wild type appearance in about half of the animals and organ defects and reduced embryonic growth in the other half. (AC) Overall appearance of representative stage 45 control specimen (A, A), or nav2 sgRNA2-injected specimen (B, B), illustrating organ malformations with edema formation in about 50% of nav2 sgRNA2 injections. Tadpoles are shown in lateral (A, B) and ventral view (A, B). (C, D) Quantification of total body length of tadpoles with organ defects (grey fraction in C), showing reduced body length when compared to control specimens (A, C). (E) Quantification of total body length of tadpoles without organ defects (dark blue fraction in C) of the two individual experiments with sgRNA2 (exp.1, n=53 animals, stage 45; exp.2, n=31 animals, stage 45) demonstrating a mild but not statistically significant increase in body size. co, control; sgRNA, single-guide RNA; mm, millimeter; OD, organ defects; st., stage; wta, wild type appearance.
Figure 1. Pedigree and height data. (A) Pedigree of family: Black symbols indicate individuals with tall stature. Individual I.2 is considered as borderline tall stature (grey symbol). White symbols indicate normal stature. Exome sequencing was carried out on DNA from individuals I.1, II.1, II.4 and III.1. DNA was also available from I.2, II.2 and III.2 but not for exome sequencing; no DNA was available from individual II.3 (declined). (B) Data on height and year of birth of Family A Height data were adjusted for secular trend and shrinking. SDS, Standard deviation score.
Figure 2. Ingenuity (IPA) Network analysis. The newly identified genes were used to show functional connections in context of known protein networks, based on data from the literature. No connections to known proteins could be established for CNGB1.
Figure 3. CRISPR/Cas-mediated knockout of nav2 causes enhanced embryonic growth. (A, B) Tadpole total body length measurements of three independent experiments. All experiments revealed a slightly increased average body size in nav2 sgRNA-injected specimens as compared to control littermates. (A) Three single experiments with sgRNA1 that specifically targets an exon orthologous to the exon harboring the human NAV2 missense mutation p.R2201C (exp.1, n=38 animals, stage 45; exp.2, n=102 animals, stage 44; exp.3, n=18 animals, stage 45); (B) Combined data of the three experiments in (A) after normalization to the mean of their controls revealed a significant increase of relative body sizes after sgRNA1 injections (p-value=0.023). Boxplot whiskers (error bars) are 1.5 * IQR +Q3 (upper), or 1.5 * IQR -Q1 (lower). co, control; exp., experiment; sgRNA, single-guide RNA; mm, millimeter.
Accogli,
Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development.
2023, Pubmed
Accogli,
Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development.
2023,
Pubmed Astori,
ARID1a Associates with Lymphoid-Restricted Transcription Factors and Has an Essential Role in T Cell Development.
2020,
Pubmed Benito-Sanz,
Clinical and molecular evaluation of SHOX/PAR1 duplications in Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS).
2011,
Pubmed Brinkman,
Easy quantitative assessment of genome editing by sequence trace decomposition.
2014,
Pubmed Caruana,
Genome-wide ENU mutagenesis in combination with high density SNP analysis and exome sequencing provides rapid identification of novel mouse models of developmental disease.
2013,
Pubmed Chen,
Crucial role of estrogen receptor-alpha interaction with transcription coregulators in follicle-stimulating hormone and transforming growth factor beta1 up-regulation of steroidogenesis in rat ovarian granulosa cells.
2008,
Pubmed Cho,
OpenCell: Endogenous tagging for the cartography of human cellular organization.
2022,
Pubmed Conant,
Inference of CRISPR Edits from Sanger Trace Data.
2022,
Pubmed Conaway,
Vitamin a metabolism, action, and role in skeletal homeostasis.
2013,
Pubmed Corredor,
Tall Stature: A Challenge for Clinicians.
2019,
Pubmed De Luca,
Retinoic acid is a potent regulator of growth plate chondrogenesis.
2000,
Pubmed Ebmeier,
Activator-Mediator binding regulates Mediator-cofactor interactions.
2010,
Pubmed Estrada,
Identifying therapeutic drug targets using bidirectional effect genes.
2021,
Pubmed Fredriks,
Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders.
2005,
Pubmed Grossmann,
Phospho-tyrosine dependent protein-protein interaction network.
2015,
Pubmed Hannema,
An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities.
2013,
Pubmed Kant,
Tall stature and duplication of the insulin-like growth factor I receptor gene.
2007,
Pubmed Kikani,
Laser Capture Microdissection of Mouse Growth Plate Cartilage.
2021,
Pubmed Kovalski,
The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2.
2019,
Pubmed Lauffer,
Towards a Rational and Efficient Diagnostic Approach in Children Referred for Tall Stature and/or Accelerated Growth to the General Paediatrician.
2019,
Pubmed Luck,
A reference map of the human binary protein interactome.
2020,
Pubmed Lui,
Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height.
2012,
Pubmed Lui,
Differential aging of growth plate cartilage underlies differences in bone length and thus helps determine skeletal proportions.
2018,
Pubmed Marchini,
A Track Record on SHOX: From Basic Research to Complex Models and Therapy.
2016,
Pubmed Miura,
An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene.
2012,
Pubmed Moreno-Mateos,
CRISPRscan: designing highly efficient sgRNAs for CRISPR-Cas9 targeting in vivo.
2015,
Pubmed
,
Xenbase Muley,
The atRA-responsive gene neuron navigator 2 functions in neurite outgrowth and axonal elongation.
2008,
Pubmed Nassa,
The RNA-mediated estrogen receptor α interactome of hormone-dependent human breast cancer cell nuclei.
2019,
Pubmed Nenni,
Xenbase: Facilitating the Use of Xenopus to Model Human Disease.
2019,
Pubmed
,
Xenbase Niewenweg,
Adult height corrected for shrinking and secular trend.
2003,
Pubmed Perrault,
Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations.
2012,
Pubmed Rouillard,
The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins.
2016,
Pubmed Rousseau,
Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia.
1994,
Pubmed Schneider,
NIH Image to ImageJ: 25 years of image analysis.
2012,
Pubmed Schönbeck,
The world's tallest nation has stopped growing taller: the height of Dutch children from 1955 to 2009.
2013,
Pubmed Thomas,
Clinical and molecular characterization of duplications encompassing the human SHOX gene reveal a variable effect on stature.
2009,
Pubmed Toydemir,
A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome.
2006,
Pubmed Wang,
NAV2 positively modulates inflammatory response of fibroblast-like synoviocytes through activating Wnt/β-catenin signaling pathway in rheumatoid arthritis.
2021,
Pubmed Wang,
Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature.
2015,
Pubmed Weiss,
Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes.
2021,
Pubmed Yengo,
A saturated map of common genetic variants associated with human height.
2022,
Pubmed Zahn,
Normal Table of Xenopus development: a new graphical resource.
2022,
Pubmed
,
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