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194 results on '"Van Ham, Tjakko J."'

1. Biallelic NDC1 variants that interfere with ALADIN binding are associated with neuropathy and triple A-like syndrome

Author

Smits, Daphne J., Dekker, Jordy, Douben, Hannie, Schot, Rachel, Magee, Helen, Bakhtiari, Somayeh, Koehler, Katrin, Huebner, Angela, Schuelke, Markus, Darvish, Hossein, Vosoogh, Shohreh, Tafakhori, Abbas, Jameie, Melika, Taghiabadi, Ehsan, Wilson, Yana, Shah, Margit, van Slegtenhorst, Marjon A., Medici-van den Herik, Evita G., van Ham, Tjakko J., Kruer, Michael C., and Mancini, Grazia M.S.

Published
2024
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2. AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model

Author

Deng, Ruizhi, Medico-Salsench, Eva, Nikoncuk, Anita, Ramakrishnan, Reshmi, Lanko, Kristina, Kühn, Nikolas A., van der Linde, Herma C., Lor-Zade, Sarah, Albuainain, Fatimah, Shi, Yuwei, Yousefi, Soheil, Capo, Ivan, van den Herik, Evita Medici, van Slegtenhorst, Marjon, van Minkelen, Rick, Geeven, Geert, Mulder, Monique T., Ruijter, George J. G., Lütjohann, Dieter, Jacobs, Edwin H., Houlden, Henry, Pagnamenta, Alistair T., Metcalfe, Kay, Jackson, Adam, Banka, Siddharth, De Simone, Lenika, Schwaede, Abigail, Kuntz, Nancy, Palculict, Timothy Blake, Abbas, Safdar, Umair, Muhammad, AlMuhaizea, Mohammed, Colak, Dilek, AlQudairy, Hanan, Alsagob, Maysoon, Pereira, Catarina, Trunzo, Roberta, Karageorgou, Vasiliki, Bertoli-Avella, Aida M., Bauer, Peter, Bouman, Arjan, Hoefsloot, Lies H., van Ham, Tjakko J., Issa, Mahmoud, Zaki, Maha S., Gleeson, Joseph G., Willemsen, Rob, Kaya, Namik, Arold, Stefan T., Maroofian, Reza, Sanderson, Leslie E., and Barakat, Tahsin Stefan

Published
2023
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5. Dominant-acting CSF1R variants cause microglial depletion and altered astrocytic phenotype in zebrafish and adult-onset leukodystrophy

Author

Berdowski, Woutje M., van der Linde, Herma C., Breur, Marjolein, Oosterhof, Nynke, Beerepoot, Shanice, Sanderson, Leslie, Wijnands, Lieve I., de Jong, Patrick, Tsai-Meu-Chong, Elisa, de Valk, Walter, de Witte, Moniek, van IJcken, Wilfred F. J., Demmers, Jeroen, van der Knaap, Marjo S., Bugiani, Marianna, Wolf, Nicole I., and van Ham, Tjakko J.

Published
2022
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8. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author

Perenthaler, Elena, Nikoncuk, Anita, Yousefi, Soheil, Berdowski, Woutje M., Alsagob, Maysoon, Capo, Ivan, van der Linde, Herma C., van den Berg, Paul, Jacobs, Edwin H., Putar, Darija, Ghazvini, Mehrnaz, Aronica, Eleonora, van IJcken, Wilfred F. J., de Valk, Walter G., Medici-van den Herik, Evita, van Slegtenhorst, Marjon, Brick, Lauren, Kozenko, Mariya, Kohler, Jennefer N., Bernstein, Jonathan A., Monaghan, Kristin G., Begtrup, Amber, Torene, Rebecca, Al Futaisi, Amna, Al Murshedi, Fathiya, Mani, Renjith, Al Azri, Faisal, Kamsteeg, Erik-Jan, Mojarrad, Majid, Eslahi, Atieh, Khazaei, Zaynab, Darmiyan, Fateme Massinaei, Doosti, Mohammad, Karimiani, Ehsan Ghayoor, Vandrovcova, Jana, Zafar, Faisal, Rana, Nuzhat, Kandaswamy, Krishna K., Hertecant, Jozef, Bauer, Peter, AlMuhaizea, Mohammed A., Salih, Mustafa A., Aldosary, Mazhor, Almass, Rawan, Al-Quait, Laila, Qubbaj, Wafa, Coskun, Serdar, Alahmadi, Khaled O., Hamad, Muddathir H. A., Alwadaee, Salem, Awartani, Khalid, Dababo, Anas M., Almohanna, Futwan, Colak, Dilek, Dehghani, Mohammadreza, Mehrjardi, Mohammad Yahya Vahidi, Gunel, Murat, Ercan-Sencicek, A. Gulhan, Passi, Gouri Rao, Cheema, Huma Arshad, Efthymiou, Stephanie, Houlden, Henry, Bertoli-Avella, Aida M., Brooks, Alice S., Retterer, Kyle, Maroofian, Reza, Kaya, Namik, van Ham, Tjakko J., and Barakat, Tahsin Stefan

Published
2020
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9. Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization

Author

Ruijmbeek, Claudine W.B., primary, Housley, Filomena, additional, Idrees, Hafiza, additional, Housley, Michael P., additional, Pestel, Jenny, additional, Keller, Leonie, additional, Lai, Jason K.H., additional, der Linde, Herma C. van, additional, Willemsen, Rob, additional, Piesker, Janett, additional, Al-Hassnan, Zuhair N., additional, Almesned, Abdulrahman, additional, Dalinghaus, Michiel, additional, den Bersselaar, Lisa M. van, additional, van Slegtenhorst, Marjon A., additional, Tessadori, Federico, additional, Bakkers, Jeroen, additional, van Ham, Tjakko J., additional, Stainier, Didier Y.R., additional, Verhagen, Judith M.A., additional, and Reischauer, Sven, additional

Published
2023
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10. Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization

Author

Ruijmbeek, Claudine Wb, Housley, Filomena, Idrees, Hafiza, Housley, Michael P, Pestel, Jenny, Keller, Leonie, Lai, Jason Kh, der Linde, Herma C van, Willemsen, Rob, Piesker, Janett, Al-Hassnan, Zuhair N, Almesned, Abdulrahman, Dalinghaus, Michiel, den Bersselaar, Lisa M van, van Slegtenhorst, Marjon A, Tessadori, Federico, Bakkers, Jeroen, van Ham, Tjakko J, Stainier, Didier Yr, Verhagen, Judith Ma, Reischauer, Sven, Ruijmbeek, Claudine Wb, Housley, Filomena, Idrees, Hafiza, Housley, Michael P, Pestel, Jenny, Keller, Leonie, Lai, Jason Kh, der Linde, Herma C van, Willemsen, Rob, Piesker, Janett, Al-Hassnan, Zuhair N, Almesned, Abdulrahman, Dalinghaus, Michiel, den Bersselaar, Lisa M van, van Slegtenhorst, Marjon A, Tessadori, Federico, Bakkers, Jeroen, van Ham, Tjakko J, Stainier, Didier Yr, Verhagen, Judith Ma, and Reischauer, Sven

Abstract

Pediatric cardiomyopathy (CM) represents a group of rare, severe disorders that affect the myocardium. To date, the etiology and mechanisms underlying pediatric CM are incompletely understood, hampering accurate diagnosis and individualized therapy development. Here, we identified biallelic variants in the highly conserved flightless-I (FLII) gene in 3 families with idiopathic, early-onset dilated CM. We demonstrated that patient-specific FLII variants, when brought into the zebrafish genome using CRISPR/Cas9 genome editing, resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in our patients. Importantly, using these genetic animal models, complemented with in-depth loss-of-function studies, we provided insights into the function of Flii during ventricular chamber morphogenesis in vivo, including myofibril organization and cardiomyocyte cell adhesion, as well as trabeculation. In addition, we identified Flii function to be important for the regulation of Notch and Hippo signaling, crucial pathways associated with cardiac morphogenesis and function. Taken together, our data provide experimental evidence for a role for FLII in the pathogenesis of pediatric CM and report biallelic variants as a genetic cause of pediatric CM.

Published
2023

11. SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes

Author

Smits, Daphne J., Schot, Rachel, Krusy, Nathalie, Wiegmann, Katja, Utermöhlen, Olaf, Mulder, Monique T., den Hoedt, Sandra, Yoon, Grace, Deshwar, Ashish R., Kresge, Christina, Pletcher, Beth, van Mook, Maura, Ferreira, Marta Serio, Poot, Raymond A., Slotman, Johan A., Kremers, Gert Jan, Ahmad, Abeer, Albash, Buthaina, Bastaki, Laila, Marafi, Dana, Dekker, Jordy, van Ham, Tjakko J., Nguyen, Laurent, Mancini, Grazia M.S., Smits, Daphne J., Schot, Rachel, Krusy, Nathalie, Wiegmann, Katja, Utermöhlen, Olaf, Mulder, Monique T., den Hoedt, Sandra, Yoon, Grace, Deshwar, Ashish R., Kresge, Christina, Pletcher, Beth, van Mook, Maura, Ferreira, Marta Serio, Poot, Raymond A., Slotman, Johan A., Kremers, Gert Jan, Ahmad, Abeer, Albash, Buthaina, Bastaki, Laila, Marafi, Dana, Dekker, Jordy, van Ham, Tjakko J., Nguyen, Laurent, and Mancini, Grazia M.S.

Abstract

Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder with progressive congenital microcephaly and early death. SMPD4 encodes a sphingomyelinase that hydrolyses sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes (NPC). We refine the clinical phenotype of loss-of-function SMPD4 variants by describing five individuals from three unrelated families with longitudinal data due to prolonged survival. All individuals surviving beyond infancy developed insulin-dependent diabetes, besides presenting with a severe neurodevelopmental disorder and microcephaly, making diabetes one of the most frequent age-dependent non-cerebral abnormalities. We studied the function of SMPD4 at the cellular and organ levels. Knock-down of SMPD4 in human neural stem cells causes reduced proliferation rates and prolonged mitosis. Moreover, SMPD4 depletion results in abnormal nuclear envelope breakdown and reassembly during mitosis and decreased post-mitotic NPC insertion. Fibroblasts from affected individuals show deficient SMPD4-specific neutral sphingomyelinase activity, without changing (sub)cellular lipidome fractions, which suggests a local function of SMPD4 on the nuclear envelope. In embryonic mouse brain, knockdown of Smpd4 impairs cortical progenitor proliferation and induces premature differentiation by altering the balance between neurogenic and proliferative progenitor cell divisions. We hypothesize that, in individuals with SMPD4-related disease, nuclear envelope bending, which is needed to insert NPCs in the nuclear envelope, is impaired in the absence of SMPD4 and interferes with cerebral corticogenesis and survival of pancreatic beta cells.

Published
2023

12. Unexplained mismatch repair deficiency:Case closed

Author

Eikenboom, Ellis L., Moen, Sarah, van Leeuwen, Lotte, Geurts-Giele, Willemina R.R., Tops, Carli M.J., van Ham, Tjakko J., Dinjens, Winand N.M., Dubbink, Hendrikus J., Spaander, Manon C.W., Wagner, Anja, Eikenboom, Ellis L., Moen, Sarah, van Leeuwen, Lotte, Geurts-Giele, Willemina R.R., Tops, Carli M.J., van Ham, Tjakko J., Dinjens, Winand N.M., Dubbink, Hendrikus J., Spaander, Manon C.W., and Wagner, Anja

Abstract

To identify Lynch syndrome (LS) carriers, DNA mismatch repair (MMR) immunohistochemistry (IHC) is performed on colorectal cancers (CRCs). Upon subsequent LS diagnostics, MMR deficiency (MMRd) sometimes remains unexplained (UMMRd). Recently, the importance of complete LS diagnostics to explain UMMRd, involving MMR methylation, germline, and somatic analyses, was stressed. To explore why some MMRd CRCs remain unsolved, we performed a systematic review of the literature and mapped patients with UMMRd diagnosed in our center. A systematic literature search was performed in Ovid Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar for articles on UMMRd CRCs after complete LS diagnostics published until December 15, 2021. Additionally, UMMRd CRCs diagnosed in our center since 1993 were mapped. Of 754 identified articles, 17 were included, covering 74 patients with UMMRd. Five CRCs were microsatellite stable. Upon complete diagnostics, 39 patients had single somatic MMR hits, and six an MMR germline variant of unknown significance (VUS). Ten had somatic pathogenic variants (PVs) in POLD1, MLH3, MSH3, and APC. The remaining 14 patients were the only identifiable cases in the literature without a plausible identified cause of the UMMRd. Of those, nine were suspected to have LS. In our center, complete LS diagnostics in approximately 5,000 CRCs left seven MMRd CRCs unexplained. All had a somatic MMR hit or MMR germline VUS, indicative of a missed second MMR hit. In vitually all patients with UMMRd, complete LS diagnostics suggest MMR gene involvement. Optimizing detection of currently undetectable PVs and VUS interpretation might explain all UMMRd CRCs, considering UMMRd a case closed.

Published
2023

13. Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization

Author

Cancer, Child Health, Cardiologie onderzoek 2, Onderzoek, Circulatory Health, Ruijmbeek, Claudine W.B., Housley, Filomena, Idrees, Hafiza, Housley, Michael P., Pestel, Jenny, Keller, Leonie, Lai, Jason K.H., van der Linde, Herma C., Willemsen, Rob, Piesker, Janett, Al-Hassnan, Zuhair N., Almesned, Abdulrahman, Dalinghaus, Michiel, van den Bersselaar, Lisa M., van Slegtenhorst, Marjon A., Tessadori, Federico, Bakkers, Jeroen, van Ham, Tjakko J., Stainier, Didier Y.R., Verhagen, Judith M.A., Reischauer, Sven, Cancer, Child Health, Cardiologie onderzoek 2, Onderzoek, Circulatory Health, Ruijmbeek, Claudine W.B., Housley, Filomena, Idrees, Hafiza, Housley, Michael P., Pestel, Jenny, Keller, Leonie, Lai, Jason K.H., van der Linde, Herma C., Willemsen, Rob, Piesker, Janett, Al-Hassnan, Zuhair N., Almesned, Abdulrahman, Dalinghaus, Michiel, van den Bersselaar, Lisa M., van Slegtenhorst, Marjon A., Tessadori, Federico, Bakkers, Jeroen, van Ham, Tjakko J., Stainier, Didier Y.R., Verhagen, Judith M.A., and Reischauer, Sven

Published
2023

14. SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes

Author

Smits, Daphne J, primary, Schot, Rachel, additional, Krusy, Nathalie, additional, Wiegmann, Katja, additional, Utermöhlen, Olaf, additional, Mulder, Monique T, additional, den Hoedt, Sandra, additional, Yoon, Grace, additional, Deshwar, Ashish R, additional, Kresge, Christina, additional, Pletcher, Beth, additional, van Mook, Maura, additional, Ferreira, Marta Serio, additional, Poot, Raymond A, additional, Slotman, Johan A, additional, Kremers, Gert-Jan, additional, Ahmad, Abeer, additional, Albash, Buthaina, additional, Bastaki, Laila, additional, Marafi, Dana, additional, Dekker, Jordy, additional, van Ham, Tjakko J, additional, Nguyen, Laurent, additional, and Mancini, Grazia M S, additional

Published
2023
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15. Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders

Author

Dekker, Jordy, primary, Schot, Rachel, additional, Bongaerts, Michiel, additional, de Valk, Walter G., additional, van Veghel-Plandsoen, Monique M., additional, Monfils, Kathryn, additional, Douben, Hannie, additional, Elfferich, Peter, additional, Kasteleijn, Esmee, additional, van Unen, Leontine M.A., additional, Geeven, Geert, additional, Saris, Jasper J., additional, van Ierland, Yvette, additional, Verheijen, Frans W., additional, van der Sterre, Marianne L.T., additional, Sadeghi Niaraki, Farah, additional, Smits, Daphne J., additional, Huidekoper, Hidde H., additional, Williams, Monique, additional, Wilke, Martina, additional, Verhoeven, Virginie J.M., additional, Joosten, Marieke, additional, Kievit, Anneke J.A., additional, van de Laar, Ingrid M.B.H., additional, Hoefsloot, Lies H., additional, Hoogeveen-Westerveld, Marianne, additional, Nellist, Mark, additional, Mancini, Grazia M.S., additional, and van Ham, Tjakko J., additional

Published
2023
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16. CLEC16A interacts with retromer and TRIM27, and its loss impairs endosomal trafficking and neurodevelopment

Author

Smits, Daphne J., primary, Dekker, Jordy, additional, Schot, Rachel, additional, Tabarki, Brahim, additional, Alhashem, Amal, additional, Demmers, Jeroen A. A., additional, Dekkers, Dick H. W., additional, Romito, Antonio, additional, van der Spek, Peter J., additional, van Ham, Tjakko J., additional, Bertoli-Avella, Aida M., additional, and Mancini, Grazia M. S., additional

Published
2022
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17. Noncoding Aberrations in Mismatch Repair Genes Underlie a Substantial Part of the Missing Heritability in Lynch Syndrome

Author

Te Paske, Iris B.A.W., primary, Mensenkamp, Arjen R., additional, Neveling, Kornelia, additional, Hoogerbrugge, Nicoline, additional, Ligtenberg, Marjolijn J.L., additional, De Voer, Richarda M., additional, Baert-Desurmont, Stéphanie, additional, Claes, Kathleen B.M., additional, de Leeneer, Kim, additional, Elze, Lisa, additional, van den Heuvel, Simone, additional, van der Post, Rachel S., additional, van Twuijver, Yvonne, additional, van Ham, Tjakko J., additional, Wagner, Anja, additional, de Jong, Mirjam M., additional, Leter, Edward M., additional, and Nielsen, Maartje, additional

Published
2022
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18. High‐yield identification of pathogenic NF1 variants by skin fibroblast transcriptome screening after apparently normal diagnostic DNA testing

Author

Douben, Hannie C. W., primary, Nellist, Mark, additional, van Unen, Leontine, additional, Elfferich, Peter, additional, Kasteleijn, Esmee, additional, Hoogeveen‐Westerveld, Marianne, additional, Louwen, Jesse, additional, van Veghel‐Plandsoen, Monique, additional, de Valk, Walter, additional, Saris, Jasper J., additional, Hendriks, Femke, additional, Korpershoek, Esther, additional, Hoefsloot, Lies H., additional, van Vliet, Margreethe, additional, van Bever, Yolande, additional, van de Laar, Ingrid, additional, Aten, Emmelien, additional, Lachmeijer, Augusta M. A., additional, Taal, Walter, additional, van den Bersselaar, Lisa, additional, Schuurmans, Juliette, additional, Oostenbrink, Rianne, additional, van Minkelen, Rick, additional, van Ierland, Yvette, additional, and van Ham, Tjakko J., additional

Published
2022
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21. RNA-sequencing improves diagnosis for neurodevelopmental disorders by identifying pathogenic non-coding variants and reinterpretation of coding variants

Author

Dekker, Jordy, primary, Schot, Rachel, additional, Bongaerts, Michiel, additional, de Valk, Walter G., additional, van Veghel-Plandsoen, Monique M., additional, Monfils, Kathryn, additional, Douben, Hannie, additional, Elfferich, Peter, additional, Kasteleijn, Esmee, additional, van Unen, Leontine M.A., additional, Geeven, Geert, additional, Saris, Jasper J., additional, van Ierland, Yvette, additional, Verheijen, Frans W., additional, van der Sterre, Marianne L.T., additional, Niaraki, Farah Sadeghi, additional, Huidekoper, Hidde H., additional, Williams, Monique, additional, Wilke, Martina, additional, Verhoeven, Virginie J.M., additional, Joosten, Marieke, additional, Kievit, Anneke J.A., additional, van de Laar, Ingrid M.B.H., additional, Hoefsloot, Lies H., additional, Hoogeveen-Westerveld, Marianne, additional, Nellist, Mark, additional, Mancini, Grazia M.S., additional, and van Ham, Tjakko J., additional

Published
2022
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23. Three patients with defects in interferon gamma receptor signaling:A challenging diagnosis

Author

Zhou, Zijun, Hollink, Iris H I M, Bouman, Arjan, Lourens, Mirthe S, Brooimans, Rik A, van Ham, Tjakko J, Fraaij, Pieter L A, van Rossum, Annemarie M C, Zijtregtop, Eline A M, Dik, Willem A, Dalm, Virgil A S H, van Hagen, P Martin, Ijspeert, Hanna, Vermont, Clementien L, Zhou, Zijun, Hollink, Iris H I M, Bouman, Arjan, Lourens, Mirthe S, Brooimans, Rik A, van Ham, Tjakko J, Fraaij, Pieter L A, van Rossum, Annemarie M C, Zijtregtop, Eline A M, Dik, Willem A, Dalm, Virgil A S H, van Hagen, P Martin, Ijspeert, Hanna, and Vermont, Clementien L

Published
2022

24. High-yield identification of pathogenic NF1 variants by skin fibroblast transcriptome screening after apparently normal diagnostic DNA testing

Author

Douben, Hannie C.W., Nellist, Mark, van Unen, Leontine, Elfferich, Peter, Kasteleijn, Esmee, Hoogeveen-Westerveld, Marianne, Louwen, Jesse, van Veghel-Plandsoen, Monique, de Valk, Walter, Saris, Jasper J., Hendriks, Femke, Korpershoek, Esther, Hoefsloot, Lies H., van Vliet, Margreethe, van Bever, Yolande, van de Laar, Ingrid, Aten, Emmelien, Lachmeijer, Augusta M.A., Taal, Walter, van den Bersselaar, Lisa, Schuurmans, Juliette, Oostenbrink, Rianne, van Minkelen, Rick, van Ierland, Yvette, van Ham, Tjakko J., Douben, Hannie C.W., Nellist, Mark, van Unen, Leontine, Elfferich, Peter, Kasteleijn, Esmee, Hoogeveen-Westerveld, Marianne, Louwen, Jesse, van Veghel-Plandsoen, Monique, de Valk, Walter, Saris, Jasper J., Hendriks, Femke, Korpershoek, Esther, Hoefsloot, Lies H., van Vliet, Margreethe, van Bever, Yolande, van de Laar, Ingrid, Aten, Emmelien, Lachmeijer, Augusta M.A., Taal, Walter, van den Bersselaar, Lisa, Schuurmans, Juliette, Oostenbrink, Rianne, van Minkelen, Rick, van Ierland, Yvette, and van Ham, Tjakko J.

Abstract

Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in NF1. Due to the size, complexity, and high mutation rate at the NF1 locus, the identification of causative variants can be challenging. To obtain a molecular diagnosis in 15 individuals meeting diagnostic criteria for NF1, we performed transcriptome analysis (RNA-seq) on RNA obtained from cultured skin fibroblasts. In each case, routine molecular DNA diagnostics had failed to identify a disease-causing variant in NF1. A pathogenic variant or abnormal mRNA splicing was identified in 13 cases: 6 deep intronic variants and 2 transposon insertions causing noncanonical splicing, 3 postzygotic changes, 1 branch point mutation and, in 1 case, abnormal splicing for which the responsible DNA change remains to be identified. These findings helped resolve the molecular findings for an additional 17 individuals in multiple families with NF1, demonstrating the utility of skin-fibroblast-based transcriptome analysis for molecular diagnostics. RNA-seq improves mutation detection in NF1 and provides a powerful complementary approach to DNA-based methods. Importantly, our approach is applicable to other genetic disorders, particularly those caused by a wide variety of variants in a limited number of genes and specifically for individuals in whom routine molecular DNA diagnostics did not identify the causative variant.

Published
2022

25. Dominant-acting CSF1R variants cause microglial depletion and altered astrocytic phenotype in zebrafish and adult-onset leukodystrophy

Author

CTI De Witte, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Berdowski, Woutje M, van der Linde, Herma C, Breur, Marjolein, Oosterhof, Nynke, Beerepoot, Shanice, Sanderson, Leslie, Wijnands, Lieve I, de Jong, Patrick, Tsai-Meu-Chong, Elisa, de Valk, Walter, de Witte, Moniek, van IJcken, Wilfred F J, Demmers, Jeroen, van der Knaap, Marjo S, Bugiani, Marianna, Wolf, Nicole I, van Ham, Tjakko J, CTI De Witte, MS Hematologie, Infection & Immunity, Regenerative Medicine and Stem Cells, Cancer, Berdowski, Woutje M, van der Linde, Herma C, Breur, Marjolein, Oosterhof, Nynke, Beerepoot, Shanice, Sanderson, Leslie, Wijnands, Lieve I, de Jong, Patrick, Tsai-Meu-Chong, Elisa, de Valk, Walter, de Witte, Moniek, van IJcken, Wilfred F J, Demmers, Jeroen, van der Knaap, Marjo S, Bugiani, Marianna, Wolf, Nicole I, and van Ham, Tjakko J

Published
2022

28. The multicellular interplay of microglia in health and disease: lessons from leukodystrophy

Author

Berdowski, Woutje M., Sanderson, Leslie E., and van Ham, Tjakko J.

Subjects
0301 basic medicine, leukodystrophy, Neurodegenerative Disorders, Central nervous system, Neuroscience (miscellaneous), microglia, oligodendrocytes, Medicine (miscellaneous), Review, Disease, Biology, General Biochemistry, Genetics and Molecular Biology, White matter, 03 medical and health sciences, Myelin, Rare Diseases, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Immunology and Microbiology (miscellaneous), genetic disease, Zebrafish as a Disease Model, Pathology, medicine, Animals, Humans, RB1-214, Zebrafish, Myelin Sheath, Microglia, Leukodystrophy, astrocytes, myelination, Neurodegenerative Diseases, medicine.disease, biology.organism_classification, White Matter, 3. Good health, Multicellular organism, 030104 developmental biology, medicine.anatomical_structure, Medicine, Neuroscience, 030217 neurology & neurosurgery
Abstract

Microglia are highly dynamic cells crucial for developing and maintaining lifelong brain function and health through their many interactions with essentially all cellular components of the central nervous system. The frequent connection of microglia to leukodystrophies, genetic disorders of the white matter, has highlighted their involvement in the maintenance of white matter integrity. However, the mechanisms that underlie their putative roles in these processes remain largely uncharacterized. Microglia have also been gaining attention as possible therapeutic targets for many neurological conditions, increasing the demand to understand their broad spectrum of functions and the impact of their dysregulation. In this Review, we compare the pathological features of two groups of genetic leukodystrophies: those in which microglial dysfunction holds a central role, termed ‘microgliopathies’, and those in which lysosomal or peroxisomal defects are considered to be the primary driver. The latter are suspected to have notable microglia involvement, as some affected individuals benefit from microglia-replenishing therapy. Based on overlapping pathology, we discuss multiple ways through which aberrant microglia could lead to white matter defects and brain dysfunction. We propose that the study of leukodystrophies, and their extensively multicellular pathology, will benefit from complementing analyses of human patient material with the examination of cellular dynamics in vivo using animal models, such as zebrafish. Together, this will yield important insight into the cell biological mechanisms of microglial impact in the central nervous system, particularly in the development and maintenance of myelin, that will facilitate the development of new, and refinement of existing, therapeutic options for a range of brain diseases., Summary: Microglia abnormalities are increasingly linked to white matter diseases. Complementing analyses of leukodystrophy patient material with animal models yields insight into the impact and therapeutic potential of microglia across diverse brain disorders.

Published
2021

31. Additional file 1 of Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance

Author

Yousefi, Soheil, Deng, Ruizhi, Lanko, Kristina, Salsench, Eva Medico, Nikoncuk, Anita, van der Linde, Herma C., Perenthaler, Elena, van Ham, Tjakko J., Mulugeta, Eskeatnaf, and Barakat, Tahsin Stefan

Abstract

Additional file 1: Fig. S1: Flow chart of integrative data analysis; Fig. S2: Derivation of pCRs and DAEs; Fig. S3: Enhancer-Gene predictions and target gene expression; Fig. S4: Features and motifs in DAEs and nDAEs; Fig. S5: Cell type specificity of DAEs and nDAEs; Fig. S6: Dynamics of DAEs and nDAEs in comparison to adult brain; Fig. S7: DAEs and nDAEs in human disease, related to Fig. 5; Fig. S8: Zebrafish enhancer reporter assay

Published
2021
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32. Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Author

Sanderson, Leslie E., Lanko, Kristina, Alsagob, Maysoon, Almass, Rawan, Al-Ahmadi, Nada, Najafi, Maryam, Al-Muhaizea, Mohammad A., Alzaidan, Hamad, Aldhalaan, Hesham, Perenthaler, Elena, Van Der Linde, Herma C., Nikoncuk, Anita, Kühn, Nikolas A., Antony, Dinu, Owaidah, Tarek Mustafa, Raskin, Salmo, Vieira, Luana Gabriela Dalla Rosa, Mombach, Romulo, Ahangari, Najmeh, Silveira, Tainá Regina Damaceno, Ameziane, Najim, Rolfs, Arndt, Alharbi, Aljohara, Sabbagh, Raghda M., Alahmadi, Khalid, Alawam, Bashayer, Ghebeh, Hazem, Alhargan, Aljouhra, Albader, Anoud A., Binhumaid, Faisal S., Goljan, Ewa, Monies, Dorota, Mustafa, Osama M., Aldosary, Mazhor, Albakheet, Albandary, Alyounes, Banan, Almutairi, Faten, Al-Odaib, Ali, Aksoy, Durdane Bekar, Basak, A. Nazli, Palvadeau, Robin, Trabzuni, Daniah, Rosenfeld, Jill A., Karimiani, Ehsan Ghayoor, Meyer, Brian F., Karakas, Bedri, Al-Mohanna, Futwan, Arold, Stefan T., Colak, Dilek, Maroofian, Reza, Houlden, Henry, Bertoli-Avella, Aida M., Schmidts, Miriam, Barakat, Tahsin Stefan, Van Ham, Tjakko J., Kaya, Namik, Sanderson, Leslie E., Lanko, Kristina, Alsagob, Maysoon, Almass, Rawan, Al-Ahmadi, Nada, Najafi, Maryam, Al-Muhaizea, Mohammad A., Alzaidan, Hamad, Aldhalaan, Hesham, Perenthaler, Elena, Van Der Linde, Herma C., Nikoncuk, Anita, Kühn, Nikolas A., Antony, Dinu, Owaidah, Tarek Mustafa, Raskin, Salmo, Vieira, Luana Gabriela Dalla Rosa, Mombach, Romulo, Ahangari, Najmeh, Silveira, Tainá Regina Damaceno, Ameziane, Najim, Rolfs, Arndt, Alharbi, Aljohara, Sabbagh, Raghda M., Alahmadi, Khalid, Alawam, Bashayer, Ghebeh, Hazem, Alhargan, Aljouhra, Albader, Anoud A., Binhumaid, Faisal S., Goljan, Ewa, Monies, Dorota, Mustafa, Osama M., Aldosary, Mazhor, Albakheet, Albandary, Alyounes, Banan, Almutairi, Faten, Al-Odaib, Ali, Aksoy, Durdane Bekar, Basak, A. Nazli, Palvadeau, Robin, Trabzuni, Daniah, Rosenfeld, Jill A., Karimiani, Ehsan Ghayoor, Meyer, Brian F., Karakas, Bedri, Al-Mohanna, Futwan, Arold, Stefan T., Colak, Dilek, Maroofian, Reza, Houlden, Henry, Bertoli-Avella, Aida M., Schmidts, Miriam, Barakat, Tahsin Stefan, Van Ham, Tjakko J., and Kaya, Namik

Abstract

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

Published
2021

33. Reduction of oxidative stress suppresses poly-GR-mediated toxicity in zebrafish embryos

Author

Riemslagh, Fréderike W., Verhagen, Rob F.M., van der Toorn, Esmay C., Smits, Daphne J., Quint, Wim H., van der Linde, Herma C., van Ham, Tjakko J., Willemsen, Rob, Riemslagh, Fréderike W., Verhagen, Rob F.M., van der Toorn, Esmay C., Smits, Daphne J., Quint, Wim H., van der Linde, Herma C., van Ham, Tjakko J., and Willemsen, Rob

Abstract

The hexanucleotide (G4C2)-repeat expansion in the C9ORF72 gene is the most common pathogenic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This repeat expansion can be translated into dipeptide repeat proteins (DPRs), and distribution of the poly-GR DPR correlates with neurodegeneration in postmortem C9FTD/ALS brains. Here, we assessed poly-GR toxicity in zebrafish embryos, using an annexin A5-based fluorescent transgenic line (secA5) that allows for detection and quantification of apoptosis in vivo. Microinjection of RNA encoding poly-GR into fertilized oocytes evoked apoptosis in the brain and abnormal motor neuron morphology in the trunk of 1-4-days postfertilization embryos. Poly-GR can be specifically detected in protein homogenates from injected zebrafish and in the frontal cortexes of C9FTD/ALS cases. Poly-GR expression further elevated MitoSOX levels in zebrafish embryos, indicating oxidative stress. Inhibition of reactive oxygen species using Trolox showed full suppression of poly-GR toxicity. Our study indicates that poly-GR can exert its toxicity via oxidative stress. This zebrafish model can be used to find suppressors of poly-GR toxicity and identify its molecular targets underlying neurodegeneration observed in C9FTD/ALS.

Published
2021

37. Comparative Studies in the A30P and A53T α-Synuclein C. elegans Strains to Investigate the Molecular Origins of Parkinson's Disease

Author

Perni, Michele, primary, van der Goot, Annemieke, additional, Limbocker, Ryan, additional, van Ham, Tjakko J., additional, Aprile, Francesco A., additional, Xu, Catherine K., additional, Flagmeier, Patrick, additional, Thijssen, Karen, additional, Sormanni, Pietro, additional, Fusco, Giuliana, additional, Chen, Serene W., additional, Challa, Pavan K., additional, Kirkegaard, Julius B., additional, Laine, Romain F., additional, Ma, Kai Yu, additional, Müller, Martin B. D., additional, Sinnige, Tessa, additional, Kumita, Janet R., additional, Cohen, Samuel I. A., additional, Seinstra, Renée, additional, Kaminski Schierle, Gabriele S., additional, Kaminski, Clemens F., additional, Barbut, Denise, additional, De Simone, Alfonso, additional, Knowles, Tuomas P. J., additional, Zasloff, Michael, additional, Nollen, Ellen A. A., additional, Vendruscolo, Michele, additional, and Dobson, Christopher M., additional

Published
2021
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38. Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Author

Sanderson, Leslie E, primary, Lanko, Kristina, additional, Alsagob, Maysoon, additional, Almass, Rawan, additional, Al-Ahmadi, Nada, additional, Najafi, Maryam, additional, Al-Muhaizea, Mohammad A, additional, Alzaidan, Hamad, additional, AlDhalaan, Hesham, additional, Perenthaler, Elena, additional, van der Linde, Herma C, additional, Nikoncuk, Anita, additional, Kühn, Nikolas A, additional, Antony, Dinu, additional, Owaidah, Tarek Mustafa, additional, Raskin, Salmo, additional, Vieira, Luana Gabriela Dalla Rosa, additional, Mombach, Romulo, additional, Ahangari, Najmeh, additional, Silveira, Tainá Regina Damaceno, additional, Ameziane, Najim, additional, Rolfs, Arndt, additional, Alharbi, Aljohara, additional, Sabbagh, Raghda M, additional, AlAhmadi, Khalid, additional, Alawam, Bashayer, additional, Ghebeh, Hazem, additional, AlHargan, Aljouhra, additional, Albader, Anoud A, additional, Binhumaid, Faisal S, additional, Goljan, Ewa, additional, Monies, Dorota, additional, Mustafa, Osama M, additional, Aldosary, Mazhor, additional, AlBakheet, Albandary, additional, Alyounes, Banan, additional, Almutairi, Faten, additional, Al-Odaib, Ali, additional, Aksoy, Durdane Bekar, additional, Basak, A Nazli, additional, Palvadeau, Robin, additional, Trabzuni, Daniah, additional, Rosenfeld, Jill A, additional, Karimiani, Ehsan Ghayoor, additional, Meyer, Brian F, additional, Karakas, Bedri, additional, Al-Mohanna, Futwan, additional, Arold, Stefan T, additional, Colak, Dilek, additional, Maroofian, Reza, additional, Houlden, Henry, additional, Bertoli-Avella, Aida M, additional, Schmidts, Miriam, additional, Barakat, Tahsin Stefan, additional, van Ham, Tjakko J, additional, and Kaya, Namik, additional

Published
2021
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39. Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes.

Author

Kuil, Laura E., Oosterhof, Nynke, Ferrero, Giuliano, Mikulášová, Tereza, Hason, Martina, Dekker, Jordy, Rovira, Mireia, van der Linde, Herma C, van Strien, Paulina Mh, de Pater, Emma, Schaaf, Gerben, Bindels, Erik Mj, Wittamer, Valérie, van Ham, Tjakko J, Kuil, Laura E., Oosterhof, Nynke, Ferrero, Giuliano, Mikulášová, Tereza, Hason, Martina, Dekker, Jordy, Rovira, Mireia, van der Linde, Herma C, van Strien, Paulina Mh, de Pater, Emma, Schaaf, Gerben, Bindels, Erik Mj, Wittamer, Valérie, and van Ham, Tjakko J

Abstract

Macrophages derive from multiple sources of hematopoietic progenitors. Most macrophages require colony-stimulating factor 1 receptor (CSF1R), but some macrophages persist in the absence of CSF1R. Here, we analyzed mpeg1:GFP-expressing macrophages in csf1r-deficient zebrafish and report that embryonic macrophages emerge followed by their developmental arrest. In larvae, mpeg1+ cell numbers then increased showing two distinct types in the skin: branched, putative Langerhans cells, and amoeboid cells. In contrast, although numbers also increased in csf1r-mutants, exclusively amoeboid mpeg1+ cells were present, which we showed by genetic lineage tracing to have a non-hematopoietic origin. They expressed macrophage-associated genes, but also showed decreased phagocytic gene expression and increased epithelial-associated gene expression, characteristic of metaphocytes, recently discovered ectoderm-derived cells. We further demonstrated that juvenile csf1r-deficient zebrafish exhibit systemic macrophage depletion. Thus, csf1r deficiency disrupts embryonic to adult macrophage development. Zebrafish deficient for csf1r are viable and permit analyzing the consequences of macrophage loss throughout life., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2020

41. Three patients with defects in interferon gamma receptor signaling: A challenging diagnosis.

Author

Zhou, Zijun, Hollink, Iris H. I. M., Bouman, Arjan, Lourens, Mirthe S., Brooimans, Rik A., van Ham, Tjakko J., Fraaij, Pieter L. A., van Rossum, Annemarie M. C., Zijtregtop, Eline A. M., Dik, Willem A., Dalm, Virgil A. S. H., van Hagen, P. Martin, Ijspeert, Hanna, and Vermont, Clementien L.

Subjects
INTERFERON receptors, INTERFERON gamma, LYMPHADENITIS
Published
2022
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43. Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes

Author

Kuil, Laura E, primary, Oosterhof, Nynke, additional, Ferrero, Giuliano, additional, Mikulášová, Tereza, additional, Hason, Martina, additional, Dekker, Jordy, additional, Rovira, Mireia, additional, van der Linde, Herma C, additional, van Strien, Paulina MH, additional, de Pater, Emma, additional, Schaaf, Gerben, additional, Bindels, Erik MJ, additional, Wittamer, Valerie, additional, and van Ham, Tjakko J, additional

Published
2020
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44. Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes

Author

Kuil, Laura E., primary, Oosterhof, Nynke, additional, Ferrero, Giuliano, additional, Mikulášová, Tereza, additional, Hason, Martina, additional, Dekker, Jordy, additional, Rovira, Mireia, additional, van der Linde, Herma C., additional, van Strien, Paulina M.H., additional, de Pater, Emma, additional, Schaaf, Gerben, additional, Bindels, Eric M.J., additional, Wittamer, Valerie, additional, and van Ham, Tjakko J., additional

Published
2020
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45. Author response: Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes

Author

Kuil, Laura E, primary, Oosterhof, Nynke, additional, Ferrero, Giuliano, additional, Mikulášová, Tereza, additional, Hason, Martina, additional, Dekker, Jordy, additional, Rovira, Mireia, additional, van der Linde, Herma C, additional, van Strien, Paulina MH, additional, de Pater, Emma, additional, Schaaf, Gerben, additional, Bindels, Erik MJ, additional, Wittamer, Valerie, additional, and van Ham, Tjakko J, additional

Published
2020
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47. Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis

Author

Cunha, Maria Inês, primary, Su, Minhui, additional, Cantuti-Castelvetri, Ludovico, additional, Müller, Stephan A., additional, Schifferer, Martina, additional, Djannatian, Minou, additional, Alexopoulos, Ioannis, additional, van der Meer, Franziska, additional, Winkler, Anne, additional, van Ham, Tjakko J., additional, Schmid, Bettina, additional, Lichtenthaler, Stefan F., additional, Stadelmann, Christine, additional, and Simons, Mikael, additional

Published
2020
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48. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author

Perenthaler, Elena, primary, Nikoncuk, Anita, additional, Yousefi, Soheil, additional, Berdowski, Woutje M., additional, Alsagob, Maysoon, additional, Capo, Ivan, additional, van der Linde, Herma C., additional, van den Berg, Paul, additional, Jacobs, Edwin H., additional, Putar, Darija, additional, Ghazvini, Mehrnaz, additional, Aronica, Eleonora, additional, van IJcken, Wilfred F. J., additional, de Valk, Walter G., additional, Medici-van den Herik, Evita, additional, van Slegtenhorst, Marjon, additional, Brick, Lauren, additional, Kozenko, Mariya, additional, Kohler, Jennefer N., additional, Bernstein, Jonathan A., additional, Monaghan, Kristin G., additional, Begtrup, Amber, additional, Torene, Rebecca, additional, Al Futaisi, Amna, additional, Al Murshedi, Fathiya, additional, Mani, Renjith, additional, Al Azri, Faisal, additional, Kamsteeg, Erik-Jan, additional, Mojarrad, Majid, additional, Eslahi, Atieh, additional, Khazaei, Zaynab, additional, Darmiyan, Fateme Massinaei, additional, Doosti, Mohammad, additional, Karimiani, Ehsan Ghayoor, additional, Vandrovcova, Jana, additional, Zafar, Faisal, additional, Rana, Nuzhat, additional, Kandaswamy, Krishna K., additional, Hertecant, Jozef, additional, Bauer, Peter, additional, AlMuhaizea, Mohammed A., additional, Salih, Mustafa A., additional, Aldosary, Mazhor, additional, Almass, Rawan, additional, Al-Quait, Laila, additional, Qubbaj, Wafa, additional, Coskun, Serdar, additional, Alahmadi, Khaled O., additional, Hamad, Muddathir H. A., additional, Alwadaee, Salem, additional, Awartani, Khalid, additional, Dababo, Anas M., additional, Almohanna, Futwan, additional, Colak, Dilek, additional, Dehghani, Mohammadreza, additional, Mehrjardi, Mohammad Yahya Vahidi, additional, Gunel, Murat, additional, Ercan-Sencicek, A. Gulhan, additional, Passi, Gouri Rao, additional, Cheema, Huma Arshad, additional, Efthymiou, Stephanie, additional, Houlden, Henry, additional, Bertoli-Avella, Aida M., additional, Brooks, Alice S., additional, Retterer, Kyle, additional, Maroofian, Reza, additional, Kaya, Namik, additional, van Ham, Tjakko J., additional, and Barakat, Tahsin Stefan, additional

Published
2019
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49. Macrophages Do Not Express the Phagocytic Receptor BAI1

Author

Hsiao, Cheng-Chih, van der Poel, Marlijn, van Ham, Tjakko J, Hamann, Jörg, Netherlands Institute for Neuroscience (NIN), and Hubrecht Institute for Developmental Biology and Stem Cell Research

Published
2019

50. Human ITGAV variants are associated with immune dysregulation, brain abnormalities, and colitis

Author

Ghasempour, Sina, Warner, Neil, Guan, Rei, Rodari, Marco M., Ivanochko, Danton, Whittaker Hawkins, Ryder, Marwaha, Ashish, Nowak, Jan K., Liang, Yijing, Mulder, Daniel J., Stallard, Lorraine, Li, Michael, Yu, Daniel D., Pluthero, Fred G., Batura, Vritika, Zhao, Mo, Siddiqui, Iram, Upton, Julia E.M., Hulst, Jessie M., Kahr, Walter H.A., Mendoza-Londono, Roberto, Charbit-Henrion, Fabienne, Hoefsloot, Lies H., Khiat, Anis, Moreira, Diana, Trindade, Eunice, Espinheira, Maria do Céu, Pinto Pais, Isabel, Weerts, Marjolein J.A., Douben, Hannie, Kotlarz, Daniel, Snapper, Scott B., Klein, Christoph, Dowling, James J., Julien, Jean-Philippe, Joosten, Marieke, Cerf-Bensussan, Nadine, Freeman, Spencer A., Parlato, Marianna, van Ham, Tjakko J., and Muise, Aleixo M.

Abstract

Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β–dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function.

Published
2024
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