Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes

Weiß, Birgit; Eberle, Birgit; Roeth, Ralph; Bruin, Christiaan de; Lui, Julian C.; Paramasivam, Nagarajan; Hinderhofer, Katrin; Duyvenvoorde, Hermine A. van; Baron, Jeffrey; Wit, Jan M.; Rappold, Gudrun

doi:10.3389/fendo.2021.660731

Cited by 6 publications

(8 citation statements)

References 34 publications

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“…After we identified the candidate genes in this family, we re-examined exome sequencing data from a previously reported Dutch family with tall stature ( 12 ) and identified a rare NAV2 variant in two family members, but not in the other candidate genes of the current study. This NAV2 variant [c.G6112A, p.(E2038K)] was predicted as probably damaging by PPH2, damaging by Provean, deleterious by Sift and disease-causing by Mutation taster, with a CADD score of 26.8.…”

Section: Resultsmentioning

confidence: 90%

“…To further address the biological relevance of the identified gene variants, network analysis by Ingenuity Pathway Analysis (IPA) was carried out. IPA was used on the six novel candidate genes for tall stature together with 86 genes previously associated with tall stature by GWAS and literature data ( Supplementary Table 4 ) ( 12 , 20 , 21 ). The newly identified six candidate genes were analysed to assess whether functional connections exist with known protein networks ( Figure 2 ; Supplementary Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Candidate genes identified in this study were also checked in all tall family members that we previously described in Weiss et al, 2021 ( 12 ).…”

Section: Methodsmentioning

confidence: 99%

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Identification of novel genes including NAV2 associated with isolated tall stature

Weiss,

Ott,

Vick

et al. 2023

Front. Endocrinol.

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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.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

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Identification of novel genes including NAV2 associated with isolated tall stature

Weiss,

Ott,

Vick

et al. 2023

Front. Endocrinol.

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“…At the physiological level, the cellular functions of TSTD2 protein are still unknown. TSTD2’s gene expression or protein accumulation variations were reported for human traits or diseases resistance/susceptibility, but, to date, this information is too preliminary to propose physiological implications [ 90 , 91 , 92 ].…”

Section: The Class Three Rhd Enzymes In Humans the Most Versatile Rhd...mentioning

confidence: 99%

Rhodanese-Fold Containing Proteins in Humans: Not Just Key Players in Sulfur Trafficking

et al. 2023

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The Rhodanese-fold is a ubiquitous structural domain present in various protein subfamilies associated with different physiological functions or pathophysiological conditions in humans. Proteins harboring a Rhodanese domain are diverse in terms of domain architecture, with some representatives exhibiting one or several Rhodanese domains, fused or not to other structural domains. The most famous Rhodanese domains are catalytically active, thanks to an active-site loop containing an essential cysteine residue which allows for catalyzing sulfur transfer reactions involved in sulfur trafficking, hydrogen sulfide metabolism, biosynthesis of molybdenum cofactor, thio-modification of tRNAs or protein urmylation. In addition, they also catalyse phosphatase reactions linked to cell cycle regulation, and recent advances proposed a new role into tRNA hydroxylation, illustrating the catalytic versatility of Rhodanese domain. To date, no exhaustive analysis of Rhodanese containing protein equipment from humans is available. In this review, we focus on structural and biochemical properties of human-active Rhodanese-containing proteins, in order to provide a picture of their established or putative key roles in many essential biological functions.

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“…Protein-protein interactions between gene products can modulate the overall function and stability of protein complexes or signaling pathways [11]. Disruption of these interactions due to mutations in multiple genes can lead to aberrant cellular processes and disease manifestation.…”

Section: Complex Interactions In Oligogenic Disordersmentioning

confidence: 99%

Digenic or oligogenic mutations in presumed monogenic disorders: A review

et al. 2023

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Monogenic disorders are traditionally attributed to the presence of mutations in a single gene. However, recent advancements in genomics have revealed instances where the phenotypic expression of apparently monogenic disorders cannot be fully explained by mutations in a single gene alone. This review article aims to explore the emerging concept of digenic or oligogenic inheritance in seemingly monogenic disorders. We discuss the underlying mechanisms, clinical implications, and the challenges associated with deciphering the contribution of multiple genes in the development and manifestation of such disorders. We present relevant studies and highlight the importance of adopting a broader genetic approach in understanding the complex genetic architecture of these conditions.

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Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes

Cited by 6 publications

References 34 publications

Identification of novel genes including NAV2 associated with isolated tall stature

Identification of novel genes including NAV2 associated with isolated tall stature

Rhodanese-Fold Containing Proteins in Humans: Not Just Key Players in Sulfur Trafficking

Digenic or oligogenic mutations in presumed monogenic disorders: A review

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