HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans

Floor A. Duijkers, Andrew McDonald, Georges E. Janssens, Marco Lezzerini, Aldo Jongejan, Silvana van Koningsbruggen, Wendela G. Leeuwenburgh-Pronk, Marcin W. Wlodarski, S. bastien Moutton, Frédéric Tran-Mau-Them, Christel Thauvin-Robinet, Laurence Faivre, Kristin G. Monaghan, Thomas Smol, Odile Boute-Benejean, Roger L. Ladda, Susan L. Sell, Ange-Line Bruel, Riekelt H. Houtkooper, Alyson W. MacInnes

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other “spliceosomopathies” linked to variants that drive multi-system congenital defects and are found in hnRNPs.
Original languageEnglish
Pages (from-to)1040-1059
JournalAmerican journal of human genetics
Volume104
Issue number6
DOIs
Publication statusPublished - 2019

Cite this

Duijkers, F. A., McDonald, A., Janssens, G. E., Lezzerini, M., Jongejan, A., van Koningsbruggen, S., ... MacInnes, A. W. (2019). HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans. American journal of human genetics, 104(6), 1040-1059. https://doi.org/10.1016/j.ajhg.2019.03.024
Duijkers, Floor A. ; McDonald, Andrew ; Janssens, Georges E. ; Lezzerini, Marco ; Jongejan, Aldo ; van Koningsbruggen, Silvana ; Leeuwenburgh-Pronk, Wendela G. ; Wlodarski, Marcin W. ; Moutton, S. bastien ; Tran-Mau-Them, Frédéric ; Thauvin-Robinet, Christel ; Faivre, Laurence ; Monaghan, Kristin G. ; Smol, Thomas ; Boute-Benejean, Odile ; Ladda, Roger L. ; Sell, Susan L. ; Bruel, Ange-Line ; Houtkooper, Riekelt H. ; MacInnes, Alyson W. / HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans. In: American journal of human genetics. 2019 ; Vol. 104, No. 6. pp. 1040-1059.
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abstract = "The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other “spliceosomopathies” linked to variants that drive multi-system congenital defects and are found in hnRNPs.",
author = "Duijkers, {Floor A.} and Andrew McDonald and Janssens, {Georges E.} and Marco Lezzerini and Aldo Jongejan and {van Koningsbruggen}, Silvana and Leeuwenburgh-Pronk, {Wendela G.} and Wlodarski, {Marcin W.} and Moutton, {S. bastien} and Fr{\'e}d{\'e}ric Tran-Mau-Them and Christel Thauvin-Robinet and Laurence Faivre and Monaghan, {Kristin G.} and Thomas Smol and Odile Boute-Benejean and Ladda, {Roger L.} and Sell, {Susan L.} and Ange-Line Bruel and Houtkooper, {Riekelt H.} and MacInnes, {Alyson W.}",
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Duijkers, FA, McDonald, A, Janssens, GE, Lezzerini, M, Jongejan, A, van Koningsbruggen, S, Leeuwenburgh-Pronk, WG, Wlodarski, MW, Moutton, SB, Tran-Mau-Them, F, Thauvin-Robinet, C, Faivre, L, Monaghan, KG, Smol, T, Boute-Benejean, O, Ladda, RL, Sell, SL, Bruel, A-L, Houtkooper, RH & MacInnes, AW 2019, 'HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans' American journal of human genetics, vol. 104, no. 6, pp. 1040-1059. https://doi.org/10.1016/j.ajhg.2019.03.024

HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans. / Duijkers, Floor A.; McDonald, Andrew; Janssens, Georges E.; Lezzerini, Marco; Jongejan, Aldo; van Koningsbruggen, Silvana; Leeuwenburgh-Pronk, Wendela G.; Wlodarski, Marcin W.; Moutton, S. bastien; Tran-Mau-Them, Frédéric; Thauvin-Robinet, Christel; Faivre, Laurence; Monaghan, Kristin G.; Smol, Thomas; Boute-Benejean, Odile; Ladda, Roger L.; Sell, Susan L.; Bruel, Ange-Line; Houtkooper, Riekelt H.; MacInnes, Alyson W.

In: American journal of human genetics, Vol. 104, No. 6, 2019, p. 1040-1059.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - HNRNPR Variants that Impair Homeobox Gene Expression Drive Developmental Disorders in Humans

AU - Duijkers, Floor A.

AU - McDonald, Andrew

AU - Janssens, Georges E.

AU - Lezzerini, Marco

AU - Jongejan, Aldo

AU - van Koningsbruggen, Silvana

AU - Leeuwenburgh-Pronk, Wendela G.

AU - Wlodarski, Marcin W.

AU - Moutton, S. bastien

AU - Tran-Mau-Them, Frédéric

AU - Thauvin-Robinet, Christel

AU - Faivre, Laurence

AU - Monaghan, Kristin G.

AU - Smol, Thomas

AU - Boute-Benejean, Odile

AU - Ladda, Roger L.

AU - Sell, Susan L.

AU - Bruel, Ange-Line

AU - Houtkooper, Riekelt H.

AU - MacInnes, Alyson W.

PY - 2019

Y1 - 2019

N2 - The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other “spliceosomopathies” linked to variants that drive multi-system congenital defects and are found in hnRNPs.

AB - The heterogeneous nuclear ribonucleoprotein (HNRNP) genes code for a set of RNA-binding proteins that function primarily in the spliceosome C complex. Pathogenic variants in these genes can drive neurodegeneration, through a mechanism involving excessive stress-granule formation, or developmental defects, through mechanisms that are not known. Here, we report four unrelated individuals who have truncating or missense variants in the same C-terminal region of hnRNPR and who have multisystem developmental defects including abnormalities of the brain and skeleton, dysmorphic facies, brachydactyly, seizures, and hypoplastic external genitalia. We further identified in the literature a fifth individual with a truncating variant. RNA sequencing of primary fibroblasts reveals that these HNRNPR variants drive significant changes in the expression of several homeobox genes, as well as other transcription factors, such as LHX9, TBX1, and multiple HOX genes, that are considered fundamental regulators of embryonic and gonad development. Higher levels of retained intronic HOX sequences and lost splicing events in the HOX cluster are observed in cells carrying HNRNPR variants, suggesting that impaired splicing is at least partially driving HOX deregulation. At basal levels, stress-granule formation appears normal in primary and transfected cells expressing HNRNPR variants. However, these cells reveal profound recovery defects, where stress granules fail to disassemble properly, after exposure to oxidative stress. This study establishes an essential role for HNRNPR in human development and points to a mechanism that may unify other “spliceosomopathies” linked to variants that drive multi-system congenital defects and are found in hnRNPs.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31079900

U2 - 10.1016/j.ajhg.2019.03.024

DO - 10.1016/j.ajhg.2019.03.024

M3 - Article

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EP - 1059

JO - American journal of human genetics

JF - American journal of human genetics

SN - 0002-9297

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ER -