Identification of novel genes including NAV2 associated with isolated tall stature

Birgit Weiss; Tim Ott; Philipp Vick; Julian C Lui; Ralph Roeth; Sebastian Vogel; Stephan Waldmüller; Sandra Hoffmann; Jeffrey Baron; Jan M Wit; Gudrun A Rappold

doi:10.3389/fendo.2023.1258313

Identification of novel genes including NAV2 associated with isolated tall stature

Front Endocrinol (Lausanne). 2023 Dec 12:14:1258313. doi: 10.3389/fendo.2023.1258313. eCollection 2023.

Authors

Affiliations

¹ Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
² Department of Zoology, University of Hohenheim, Stuttgart, Germany.
³ National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.
⁴ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
⁵ Division of Pediatric Endocrinology, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands.

Abstract

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.

Keywords: IFT140; NAV2; Xenopus; all-trans retinoic acid; growth plate; isolated tall stature; oligogenic inheritance.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Height* / genetics
Bone Development
DNA Helicases* / genetics
Growth Plate
Humans
Male
Mice
Tretinoin

Substances

Tretinoin
NAV2 protein, human
Nav2 protein, mouse
DNA Helicases

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported in part by the Faculty of Medicine at Heidelberg University and the Intramural Program of the National Institute of Child Health and Human Development, National Institutes of Health. For the publication fee we acknowledge financial support by the Deutsche Forschungsgemeinschaft within the programme Open Access, as well as by Heidelberg University.