DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes

Jonathan Marquez; Nina Mann; Kathya Arana; Engin Deniz; Weizhen Ji; Monica Konstantino; Emily K. Mis; Charu Deshpande; Lauren Jeffries; Julie McGlynn; Hannah Hugo; Eugen Widmeier; Martin Konrad; Velibor Tasic; Raffaella Morotti; Julia Baptista; Sian Ellard; Saquib Ali Lakhani; Friedhelm Hildebrandt; Mustafa K. Khokha

doi:10.1136/jmedgenet-2019-106805

DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes

Jonathan Marquez, Nina Mann, Kathya Arana, Engin Deniz, Weizhen Ji, Monica Konstantino, Emily K. Mis, Charu Deshpande, Lauren Jeffries, Julie McGlynn, Hannah Hugo, Eugen Widmeier, Martin Konrad, Velibor Tasic, Raffaella Morotti, Julia Baptista, Sian Ellard, Saquib Ali Lakhani, Friedhelm Hildebrandt, Mustafa K. Khokha^*

^*Corresponding author for this work

Peninsula Medical School

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

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Abstract

BackgroundCilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.MethodsAmong individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.ResultsPatients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.ConclusionThese findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.

Original language	English
Pages (from-to)	453-464
Number of pages	0
Journal	Journal of Medical Genetics
Volume	58
Issue number	7
Early online date	6 Jul 2020
DOIs	https://doi.org/10.1136/jmedgenet-2019-106805
Publication status	Published - 27 Jul 2021

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Marquez, J., Mann, N., Arana, K., Deniz, E., Ji, W., Konstantino, M., Mis, E. K., Deshpande, C., Jeffries, L., McGlynn, J., Hugo, H., Widmeier, E., Konrad, M., Tasic, V., Morotti, R., Baptista, J., Ellard, S., Lakhani, S. A., Hildebrandt, F., & Khokha, M. K. (2021). DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes. Journal of Medical Genetics, 58(7), 453-464. https://doi.org/10.1136/jmedgenet-2019-106805

@article{cdad0c4b3d104ade9390f2463f0549bd,

title = "DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes",

abstract = "BackgroundCilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.MethodsAmong individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.ResultsPatients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.ConclusionThese findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.",

author = "Jonathan Marquez and Nina Mann and Kathya Arana and Engin Deniz and Weizhen Ji and Monica Konstantino and Mis, {Emily K.} and Charu Deshpande and Lauren Jeffries and Julie McGlynn and Hannah Hugo and Eugen Widmeier and Martin Konrad and Velibor Tasic and Raffaella Morotti and Julia Baptista and Sian Ellard and Lakhani, {Saquib Ali} and Friedhelm Hildebrandt and Khokha, {Mustafa K.}",

year = "2021",

month = jul,

day = "27",

doi = "10.1136/jmedgenet-2019-106805",

language = "English",

volume = "58",

pages = "453--464",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "7",

}

Marquez, J, Mann, N, Arana, K, Deniz, E, Ji, W, Konstantino, M, Mis, EK, Deshpande, C, Jeffries, L, McGlynn, J, Hugo, H, Widmeier, E, Konrad, M, Tasic, V, Morotti, R, Baptista, J, Ellard, S, Lakhani, SA, Hildebrandt, F & Khokha, MK 2021, 'DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes', Journal of Medical Genetics, vol. 58, no. 7, pp. 453-464. https://doi.org/10.1136/jmedgenet-2019-106805

TY - JOUR

T1 - DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes

AU - Marquez, Jonathan

AU - Mann, Nina

AU - Arana, Kathya

AU - Deniz, Engin

AU - Ji, Weizhen

AU - Konstantino, Monica

AU - Mis, Emily K.

AU - Deshpande, Charu

AU - Jeffries, Lauren

AU - McGlynn, Julie

AU - Hugo, Hannah

AU - Widmeier, Eugen

AU - Konrad, Martin

AU - Tasic, Velibor

AU - Morotti, Raffaella

AU - Baptista, Julia

AU - Ellard, Sian

AU - Lakhani, Saquib Ali

AU - Hildebrandt, Friedhelm

AU - Khokha, Mustafa K.

PY - 2021/7/27

Y1 - 2021/7/27

N2 - BackgroundCilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.MethodsAmong individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.ResultsPatients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.ConclusionThese findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.

AB - BackgroundCilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.MethodsAmong individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.ResultsPatients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.ConclusionThese findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.

U2 - 10.1136/jmedgenet-2019-106805

DO - 10.1136/jmedgenet-2019-106805

M3 - Article

SN - 0022-2593

VL - 58

SP - 453

EP - 464

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 7

ER -

DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes

Abstract

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