Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders

Siddharth Srivastava, Tejasvi Niranjan, Melanie M. May, Patrick Tarpey, William Allen, Anna Hackett, Pierre Simon Jouk, Lucy Raymond, Slyvain Briault, Cindy Skinner, Annick Toutain, Jozef Gecz, William Heath, Roger E. Stevenson, Charles E. Schwartz, Tao Wang

Research output: Contribution to journalArticle

Abstract

Background: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. Methods: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. Results: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. Conclusions: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.

LanguageEnglish
Article numbere00569
JournalMolecular Genetics and Genomic Medicine
Volume7
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • MED12
  • Mutation
  • SHH Signaling
  • XLID
  • qRT-PCR

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Srivastava, S., Niranjan, T., May, M. M., Tarpey, P., Allen, W., Hackett, A., ... Wang, T. (2019). Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders. Molecular Genetics and Genomic Medicine, 7(4), [e00569]. https://doi.org/10.1002/mgg3.569
Srivastava, Siddharth ; Niranjan, Tejasvi ; May, Melanie M. ; Tarpey, Patrick ; Allen, William ; Hackett, Anna ; Jouk, Pierre Simon ; Raymond, Lucy ; Briault, Slyvain ; Skinner, Cindy ; Toutain, Annick ; Gecz, Jozef ; Heath, William ; Stevenson, Roger E. ; Schwartz, Charles E. ; Wang, Tao. / Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders. In: Molecular Genetics and Genomic Medicine. 2019 ; Vol. 7, No. 4.
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abstract = "Background: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. Methods: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. Results: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. Conclusions: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.",
keywords = "MED12, Mutation, SHH Signaling, XLID, qRT-PCR",
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Srivastava, S, Niranjan, T, May, MM, Tarpey, P, Allen, W, Hackett, A, Jouk, PS, Raymond, L, Briault, S, Skinner, C, Toutain, A, Gecz, J, Heath, W, Stevenson, RE, Schwartz, CE & Wang, T 2019, 'Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders', Molecular Genetics and Genomic Medicine, vol. 7, no. 4, e00569. https://doi.org/10.1002/mgg3.569

Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders. / Srivastava, Siddharth; Niranjan, Tejasvi; May, Melanie M.; Tarpey, Patrick; Allen, William; Hackett, Anna; Jouk, Pierre Simon; Raymond, Lucy; Briault, Slyvain; Skinner, Cindy; Toutain, Annick; Gecz, Jozef; Heath, William; Stevenson, Roger E.; Schwartz, Charles E.; Wang, Tao.

In: Molecular Genetics and Genomic Medicine, Vol. 7, No. 4, e00569, 01.04.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders

AU - Srivastava, Siddharth

AU - Niranjan, Tejasvi

AU - May, Melanie M.

AU - Tarpey, Patrick

AU - Allen, William

AU - Hackett, Anna

AU - Jouk, Pierre Simon

AU - Raymond, Lucy

AU - Briault, Slyvain

AU - Skinner, Cindy

AU - Toutain, Annick

AU - Gecz, Jozef

AU - Heath, William

AU - Stevenson, Roger E.

AU - Schwartz, Charles E.

AU - Wang, Tao

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Background: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. Methods: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. Results: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. Conclusions: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.

AB - Background: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. Methods: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. Results: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. Conclusions: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.

KW - MED12

KW - Mutation

KW - SHH Signaling

KW - XLID

KW - qRT-PCR

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DO - 10.1002/mgg3.569

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