دورية أكاديمية
Variants in both the N- or C-terminal domains of IHH lead to defective secretion causing short stature and skeletal defects.
| العنوان: | Variants in both the N- or C-terminal domains of IHH lead to defective secretion causing short stature and skeletal defects. |
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| المؤلفون: | Díaz-González F; Institute of Medical and Molecular Genetics (INGEMM), IdiPAZ, Hospital Universitario La Paz, UAM, 28046 Madrid, Spain.; Skeletal Dysplasia Multidisciplinary Unit (UMDE-ERN BOND), Hospital Universitario La Paz, 28046 Madrid, Spain., Sentchordi-Montané L; Institute of Medical and Molecular Genetics (INGEMM), IdiPAZ, Hospital Universitario La Paz, UAM, 28046 Madrid, Spain.; Skeletal Dysplasia Multidisciplinary Unit (UMDE-ERN BOND), Hospital Universitario La Paz, 28046 Madrid, Spain.; Department of Pediatrics, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain.; Department of Pediatrics, Universidad Complutense de Madrid, 28040 Madrid, Spain., Lucas-Castro E; Institute of Medical and Molecular Genetics (INGEMM), IdiPAZ, Hospital Universitario La Paz, UAM, 28046 Madrid, Spain.; Skeletal Dysplasia Multidisciplinary Unit (UMDE-ERN BOND), Hospital Universitario La Paz, 28046 Madrid, Spain., Modamio-Høybjør S; Institute of Medical and Molecular Genetics (INGEMM), IdiPAZ, Hospital Universitario La Paz, UAM, 28046 Madrid, Spain.; Skeletal Dysplasia Multidisciplinary Unit (UMDE-ERN BOND), Hospital Universitario La Paz, 28046 Madrid, Spain., Heath KE; Institute of Medical and Molecular Genetics (INGEMM), IdiPAZ, Hospital Universitario La Paz, UAM, 28046 Madrid, Spain.; Skeletal Dysplasia Multidisciplinary Unit (UMDE-ERN BOND), Hospital Universitario La Paz, 28046 Madrid, Spain.; CIBERER, ISCIII, 28029 Madrid, Spain. |
| المصدر: | European journal of endocrinology [Eur J Endocrinol] 2024 Jul 02; Vol. 191 (1), pp. 38-46. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 9423848 Publication Model: Print Cited Medium: Internet ISSN: 1479-683X (Electronic) Linking ISSN: 08044643 NLM ISO Abbreviation: Eur J Endocrinol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2023- : Oxford : Oxford University Press Original Publication: Oslo, Norway : Scandinavian University Press, c1994- |
| مواضيع طبية MeSH: | Hedgehog Proteins*/genetics , Hedgehog Proteins*/metabolism, Humans ; Protein Domains/genetics ; Brachydactyly/genetics ; Dwarfism/genetics ; Mutation ; Animals ; Genetic Variation/genetics ; Body Height/genetics ; Heterozygote |
| مستخلص: | Background: Heterozygous Indian Hedgehog gene (IHH) variants are associated with brachydactyly type A1 (BDA1). However, in recent years, numerous variants have been identified in patients with short stature and more variable forms of brachydactyly. Many are located in the C-terminal domain of IHH (IHH-C), which lacks signaling activity but is critical for auto-cleavage and activation of the N-terminal (IHH-N) peptide. The absence of functional studies of IHH variants, particularly for those located in IHH-C, has led to these variants being classified as variants of uncertain significance (VUS). Objective: To establish a simple functional assay to determine the pathogenicity of IHH VUS and confirm that variants in the C-terminal domain affect protein function. Design/methods: In vitro studies were performed for 9 IHH heterozygous variants, to test their effect on secretion and IHH intracellular processing by western blot of cells expressing each variant. Results: IHH secretion was significantly reduced in all mutants, regardless of the location. Similarly, intracellular levels of N-terminal and C-terminal IHH peptides were severely reduced in comparison with the control. Two variants present at a relatively high frequency in the general population also reduced secretion but to a lesser degree in the heterozygous state. Conclusions: These studies provide the first evidence that variants in the C-terminal domain affect the secretion capacity of IHH and thus, reduce availability of IHH ligand, resulting in short stature and mild skeletal defects. The secretion assay permits a relatively easy test to determine the pathogenicity of IHH variants. All studied variants affected secretion and interestingly, more frequent population variants appear to have a deleterious effect and thus contribute to height variation. Competing Interests: Conflict of interest: None declared. (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) |
| معلومات مُعتمدة: | Spanish Ministry of Education |
| فهرسة مساهمة: | Keywords: IHH; C-terminal variants; brachydactyly; functional studies; short stature |
| المشرفين على المادة: | 0 (Hedgehog Proteins) 0 (IHH protein, human) |
| SCR Disease Name: | Brachydactyly type A1 |
| تواريخ الأحداث: | Date Created: 20240625 Date Completed: 20240710 Latest Revision: 20240710 |
| رمز التحديث: | 20240710 |
| DOI: | 10.1093/ejendo/lvae072 |
| PMID: | 38917024 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1479-683X |
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| DOI: | 10.1093/ejendo/lvae072 |