Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures

Shenzhao Lu; Rebecca Hernan; Paul C. Marcogliese; Yan Huang; Tracy S. Gertler; Meltem Akcaboy; Shiyong Liu; Hyung lok Chung; Xueyang Pan; Xiaoqin Sun; Melahat Melek Oguz; Ulkühan Oztoprak; Jeroen H.F. de Baaij; Jelena Ivanisevic; Erin McGinnis; Maria J. Guillen Sacoto; Wendy K. Chung; Hugo J. Bellen

doi:10.1016/j.ajhg.2022.01.020

Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures

Shenzhao Lu, Rebecca Hernan, Paul C. Marcogliese, Yan Huang, Tracy S. Gertler, Meltem Akcaboy, Shiyong Liu, Hyung lok Chung, Xueyang Pan, Xiaoqin Sun, Melahat Melek Oguz, Ulkühan Oztoprak, Jeroen H.F. de Baaij, Jelena Ivanisevic, Erin McGinnis, Maria J. Guillen Sacoto, Wendy K. Chung^*, Hugo J. Bellen

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in glia. Loss of sif reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. The TIAM1 reference (Ref) cDNA partially rescues the sif loss-of-function (LoF) phenotypes. We also assessed the function associated with three TIAM1 variants carried by two of the probands and compared them to the TIAM1 Ref cDNA function in vivo. TIAM1 p.Arg23Cys has reduced rescue ability when compared to TIAM1 Ref, suggesting that it is a partial LoF variant. In ectopic expression studies, both wild-type sif and TIAM1 Ref are toxic, whereas the three variants (p.Leu862Phe, p.Arg23Cys, and p.Gly328Val) show reduced toxicity, suggesting that they are partial LoF variants. In summary, we provide evidence that sif is important for appropriate neural function and that TIAM1 variants observed in the probands are disruptive, thus implicating loss of TIAM1 in neurological phenotypes in humans.

Original language	English (US)
Pages (from-to)	571-586
Number of pages	16
Journal	American journal of human genetics
Volume	109
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2022.01.020
State	Published - Apr 7 2022

Funding

We thank the probands and families for agreeing to participate in this study. We thank Dr. Xiao Mao for his effort in bringing us into contact with the clinicians and the family in China. We thank Dr. Sjoerd Verkaart for technical support. We thank former and present Bellen and Yamamoto lab members for their discussion and suggestions in this study, particularly Debdeep Dutta, Scott Barish, Mengqi Ma, and Yiming Zheng. We thank Ms. Hongling Pan for the injection of transgenic fly lines. We thank Dr. Michael Wangler for the guidelines for the IRB protocol. We thank the BDSC for numerous stocks. This work was supported by the Howard Hughes Medical Institute ( HHMI ), the Huffington Foundation , and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital to H.J.B. Research reported in this publication was also supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health ( NIH ) under award number P50HD103555 for use of the neurovisualization core facilities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Further support came from The Office of Research Infrastructure Programs of the NIH under the award numbers R24 OD022005 and R24 OD031447 to H.J.B. P.C.M. is supported by CIHR ( MFE-164712 ) and the Stand by Eli Foundation . H.C. is supported by Warren Alpert Foundation . We thank the probands and families for agreeing to participate in this study. We thank Dr. Xiao Mao for his effort in bringing us into contact with the clinicians and the family in China. We thank Dr. Sjoerd Verkaart for technical support. We thank former and present Bellen and Yamamoto lab members for their discussion and suggestions in this study, particularly Debdeep Dutta, Scott Barish, Mengqi Ma, and Yiming Zheng. We thank Ms. Hongling Pan for the injection of transgenic fly lines. We thank Dr. Michael Wangler for the guidelines for the IRB protocol. We thank the BDSC for numerous stocks. This work was supported by the Howard Hughes Medical Institute (HHMI), the Huffington Foundation, and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital to H.J.B. Research reported in this publication was also supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (NIH) under award number P50HD103555 for use of the neurovisualization core facilities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Further support came from The Office of Research Infrastructure Programs of the NIH under the award numbers R24 OD022005 and R24 OD031447 to H.J.B. P.C.M. is supported by CIHR (MFE-164712) and the Stand by Eli Foundation. H.C. is supported by Warren Alpert Foundation. M.J.G.S. is a salaried employee of GeneDx Inc.

Keywords

Drosophila
Sif
TIAM1
developmental delay
intellectual disability
seizures
speech delay
still life

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2022.01.020

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Lu, S., Hernan, R., Marcogliese, P. C., Huang, Y., Gertler, T. S., Akcaboy, M., Liu, S., Chung, H. L., Pan, X., Sun, X., Oguz, M. M., Oztoprak, U., de Baaij, J. H. F., Ivanisevic, J., McGinnis, E., Guillen Sacoto, M. J., Chung, W. K., & Bellen, H. J. (2022). Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures. American journal of human genetics, 109(4), 571-586. https://doi.org/10.1016/j.ajhg.2022.01.020

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title = "Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures",

abstract = "TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in glia. Loss of sif reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. The TIAM1 reference (Ref) cDNA partially rescues the sif loss-of-function (LoF) phenotypes. We also assessed the function associated with three TIAM1 variants carried by two of the probands and compared them to the TIAM1 Ref cDNA function in vivo. TIAM1 p.Arg23Cys has reduced rescue ability when compared to TIAM1 Ref, suggesting that it is a partial LoF variant. In ectopic expression studies, both wild-type sif and TIAM1 Ref are toxic, whereas the three variants (p.Leu862Phe, p.Arg23Cys, and p.Gly328Val) show reduced toxicity, suggesting that they are partial LoF variants. In summary, we provide evidence that sif is important for appropriate neural function and that TIAM1 variants observed in the probands are disruptive, thus implicating loss of TIAM1 in neurological phenotypes in humans.",

keywords = "Drosophila, Sif, TIAM1, developmental delay, intellectual disability, seizures, speech delay, still life",

author = "Shenzhao Lu and Rebecca Hernan and Marcogliese, \{Paul C.\} and Yan Huang and Gertler, \{Tracy S.\} and Meltem Akcaboy and Shiyong Liu and Chung, \{Hyung lok\} and Xueyang Pan and Xiaoqin Sun and Oguz, \{Melahat Melek\} and Ulk{\"u}han Oztoprak and \{de Baaij\}, \{Jeroen H.F.\} and Jelena Ivanisevic and Erin McGinnis and \{Guillen Sacoto\}, \{Maria J.\} and Chung, \{Wendy K.\} and Bellen, \{Hugo J.\}",

note = "Publisher Copyright: {\textcopyright} 2022 American Society of Human Genetics",

year = "2022",

month = apr,

day = "7",

doi = "10.1016/j.ajhg.2022.01.020",

language = "English (US)",

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Lu, S, Hernan, R, Marcogliese, PC, Huang, Y, Gertler, TS, Akcaboy, M, Liu, S, Chung, HL, Pan, X, Sun, X, Oguz, MM, Oztoprak, U, de Baaij, JHF, Ivanisevic, J, McGinnis, E, Guillen Sacoto, MJ, Chung, WK & Bellen, HJ 2022, 'Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures', American journal of human genetics, vol. 109, no. 4, pp. 571-586. https://doi.org/10.1016/j.ajhg.2022.01.020

TY - JOUR

T1 - Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures

AU - Lu, Shenzhao

AU - Hernan, Rebecca

AU - Marcogliese, Paul C.

AU - Huang, Yan

AU - Gertler, Tracy S.

AU - Akcaboy, Meltem

AU - Liu, Shiyong

AU - Chung, Hyung lok

AU - Pan, Xueyang

AU - Sun, Xiaoqin

AU - Oguz, Melahat Melek

AU - Oztoprak, Ulkühan

AU - de Baaij, Jeroen H.F.

AU - Ivanisevic, Jelena

AU - McGinnis, Erin

AU - Guillen Sacoto, Maria J.

AU - Chung, Wendy K.

AU - Bellen, Hugo J.

PY - 2022/4/7

Y1 - 2022/4/7

N2 - TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in glia. Loss of sif reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. The TIAM1 reference (Ref) cDNA partially rescues the sif loss-of-function (LoF) phenotypes. We also assessed the function associated with three TIAM1 variants carried by two of the probands and compared them to the TIAM1 Ref cDNA function in vivo. TIAM1 p.Arg23Cys has reduced rescue ability when compared to TIAM1 Ref, suggesting that it is a partial LoF variant. In ectopic expression studies, both wild-type sif and TIAM1 Ref are toxic, whereas the three variants (p.Leu862Phe, p.Arg23Cys, and p.Gly328Val) show reduced toxicity, suggesting that they are partial LoF variants. In summary, we provide evidence that sif is important for appropriate neural function and that TIAM1 variants observed in the probands are disruptive, thus implicating loss of TIAM1 in neurological phenotypes in humans.

AB - TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in glia. Loss of sif reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. The TIAM1 reference (Ref) cDNA partially rescues the sif loss-of-function (LoF) phenotypes. We also assessed the function associated with three TIAM1 variants carried by two of the probands and compared them to the TIAM1 Ref cDNA function in vivo. TIAM1 p.Arg23Cys has reduced rescue ability when compared to TIAM1 Ref, suggesting that it is a partial LoF variant. In ectopic expression studies, both wild-type sif and TIAM1 Ref are toxic, whereas the three variants (p.Leu862Phe, p.Arg23Cys, and p.Gly328Val) show reduced toxicity, suggesting that they are partial LoF variants. In summary, we provide evidence that sif is important for appropriate neural function and that TIAM1 variants observed in the probands are disruptive, thus implicating loss of TIAM1 in neurological phenotypes in humans.

KW - Drosophila

KW - Sif

KW - TIAM1

KW - developmental delay

KW - intellectual disability

KW - seizures

KW - speech delay

KW - still life

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UR - http://www.scopus.com/inward/citedby.url?scp=85127553899&partnerID=8YFLogxK

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DO - 10.1016/j.ajhg.2022.01.020

M3 - Article

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AN - SCOPUS:85127553899

SN - 0002-9297

VL - 109

SP - 571

EP - 586

JO - American journal of human genetics

JF - American journal of human genetics

IS - 4

ER -

Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures

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