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  Position effects at the FGF8 locus are associated with femoral hypoplasia

Socha, M., Sowińska-Seidler, A., Melo, U. S., Kragesteen, B. K., Franke, M., Heinrich, V., et al. (2021). Position effects at the FGF8 locus are associated with femoral hypoplasia. The American Journal of Human Genetics, 108(9), 1725-1734. doi:10.1016/j.ajhg.2021.08.001.

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© 2021 American Society of Human Genetics
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Socha, Magdalena , Author
Sowińska-Seidler, Anna , Author
Melo, Uirá Souto1, Author              
Kragesteen, Bjørt K. 1, Author
Franke, Martin1, Author
Heinrich, Verena2, Author              
Schöpflin, Robert, Author
Nagel, Inga, Author
Gruchy, Nicolas , Author
Mundlos, Stefan1, Author              
Sreenivasan, Varun K. A. , Author
López, Cristina , Author
Vingron, Martin3, Author              
Bukowska-Olech, Ewelina , Author
Spielmann, Malte4, Author              
Jamsheer, Aleksander , Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
3Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
4Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014183              

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Free keywords: TADs position effects FGF8 non-coding mutations femoral hypoplasia enhancer
 Abstract: Copy-number variations (CNVs) are a common cause of congenital limb malformations and are interpreted primarily on the basis of their effect on gene dosage. However, recent studies show that CNVs also influence the 3D genome chromatin organization. The functional interpretation of whether a phenotype is the result of gene dosage or a regulatory position effect remains challenging. Here, we report on two unrelated families with individuals affected by bilateral hypoplasia of the femoral bones, both harboring de novo duplications on chromosome 10q24.32. The ∼0.5 Mb duplications include FGF8, a key regulator of limb development and several limb enhancer elements. To functionally characterize these variants, we analyzed the local chromatin architecture in the affected individuals’ cells and re-engineered the duplications in mice by using CRISPR-Cas9 genome editing. We found that the duplications were associated with ectopic chromatin contacts and increased FGF8 expression. Transgenic mice carrying the heterozygous tandem duplication including Fgf8 exhibited proximal shortening of the limbs, resembling the human phenotype. To evaluate whether the phenotype was a result of gene dosage, we generated another transgenic mice line, carrying the duplication on one allele and a concurrent Fgf8 deletion on the other allele, as a control. Surprisingly, the same malformations were observed. Capture Hi-C experiments revealed ectopic interaction with the duplicated region and Fgf8, indicating a position effect. In summary, we show that duplications at the FGF8 locus are associated with femoral hypoplasia and that the phenotype is most likely the result of position effects altering FGF8 expression rather than gene dosage effects.

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Language(s): eng - English
 Dates: 2021-08-242021-09-02
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.ajhg.2021.08.001
 Degree: -

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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: 10 Volume / Issue: 108 (9) Sequence Number: - Start / End Page: 1725 - 1734 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1