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1. Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT)

Author

Riedhammer, Korbinian M., Nguyen, Thanh-Minh T., Koşukcu, Can, Calzada-Wack, Julia, Li, Yong, Assia Batzir, Nurit, Saygılı, Seha, Wimmers, Vera, Kim, Gwang-Jin, Chrysanthou, Marialena, Bakey, Zeineb, Sofrin-Drucker, Efrat, Kraiger, Markus, Sanz-Moreno, Adrián, Amarie, Oana V., Rathkolb, Birgit, Klein-Rodewald, Tanja, Garrett, Lillian, Hölter, Sabine M., Seisenberger, Claudia, Haug, Stefan, Schlosser, Pascal, Marschall, Susan, Wurst, Wolfgang, Fuchs, Helmut, Gailus-Durner, Valerie, Wuttke, Matthias, Hrabe de Angelis, Martin, Ćomić, Jasmina, Akgün Doğan, Özlem, Özlük, Yasemin, Taşdemir, Mehmet, Ağbaş, Ayşe, Canpolat, Nur, Orenstein, Naama, Çalışkan, Salim, Weber, Ruthild G., Bergmann, Carsten, Jeanpierre, Cecile, Saunier, Sophie, Lim, Tze Y., Hildebrandt, Friedhelm, Alhaddad, Bader, Basel-Salmon, Lina, Borovitz, Yael, Wu, Kaman, Antony, Dinu, Matschkal, Julia, Schaaf, Christian W., Renders, Lutz, Schmaderer, Christoph, Rogg, Manuel, Schell, Christoph, Meitinger, Thomas, Heemann, Uwe, Köttgen, Anna, Arnold, Sebastian J., Ozaltin, Fatih, Schmidts, Miriam, and Hoefele, Julia

Published
2024
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2. Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

Author

Riedhammer, Korbinian M., primary, Nguyen, Thanh-Minh T., additional, Koşukcu, Can, additional, Calzada-Wack, Julia, additional, Li, Yong, additional, Batzir, Nurit Assia, additional, Saygılı, Seha, additional, Wimmers, Vera, additional, Kim, Gwang-Jin, additional, Chrysanthou, Marialena, additional, Bakey, Zeineb, additional, Sofrin-Drucker, Efrat, additional, Kraiger, Markus, additional, Sanz-Moreno, Adrián, additional, Amarie, Oana V., additional, Rathkolb, Birgit, additional, Klein-Rodewald, Tanja, additional, Garrett, Lillian, additional, Hölter, Sabine M., additional, Seisenberger, Claudia, additional, Haug, Stefan, additional, Schlosser, Pascal, additional, Marschall, Susan, additional, Wurst, Wolfgang, additional, Fuchs, Helmut, additional, Gailus-Durner, Valerie, additional, Wuttke, Matthias, additional, Hrabe de Angelis, Martin, additional, Ćomić, Jasmina, additional, Doğan, Özlem Akgün, additional, Özlük, Yasemin, additional, Taşdemir, Mehmet, additional, Ağbaş, Ayşe, additional, Canpolat, Nur, additional, Orenstein, Naama, additional, Çalışkan, Salim, additional, Weber, Ruthild G., additional, Bergmann, Carsten, additional, Jeanpierre, Cecile, additional, Saunier, Sophie, additional, Lim, Tze Y., additional, Hildebrandt, Friedhelm, additional, Alhaddad, Bader, additional, Basel-Salmon, Lina, additional, Borovitz, Yael, additional, Wu, Kaman, additional, Antony, Dinu, additional, Matschkal, Julia, additional, Schaaf, Christian W., additional, Renders, Lutz, additional, Schmaderer, Christoph, additional, Rogg, Manuel, additional, Schell, Christoph, additional, Meitinger, Thomas, additional, Heemann, Uwe, additional, Köttgen, Anna, additional, Arnold, Sebastian J., additional, Ozaltin, Fatih, additional, Schmidts, Miriam, additional, and Hoefele, Julia, additional

Published
2023
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3. IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans

Author

Bakey, Zeineb, primary, Cabrera, Oscar A., additional, Hoefele, Julia, additional, Antony, Dinu, additional, Wu, Kaman, additional, Stuck, Michael W., additional, Micha, Dimitra, additional, Eguether, Thibaut, additional, Smith, Abigail O., additional, van der Wel, Nicole N., additional, Wagner, Matias, additional, Strittmatter, Lara, additional, Beales, Philip L., additional, Jonassen, Julie A., additional, Thiffault, Isabelle, additional, Cadieux-Dion, Maxime, additional, Boyes, Laura, additional, Sharif, Saba, additional, Tüysüz, Beyhan, additional, Dunstheimer, Desiree, additional, Niessen, Hans W. M., additional, Devine, William, additional, Lo, Cecilia W., additional, Mitchison, Hannah M., additional, Schmidts, Miriam, additional, and Pazour, Gregory J., additional

Published
2023
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5. Cleavage of periostin by MMP9 protects mice from kidney cystic disease.

Author

Djaziri, Nabila, Burel, Cindy, Abbad, Lilia, Bakey, Zeineb, Piedagnel, Rémi, and Lelongt, Brigitte

Subjects
PERIOSTIN, CYSTIC kidney disease, MATRIX metalloproteinases, POLYCYSTIC kidney disease, RENAL fibrosis
Abstract

The matrix metalloproteinase MMP9 influences cellular morphology and function, and plays important roles in organogenesis and disease. It exerts both protective and deleterious effects in renal pathology, depending upon its specific substrates. To explore new functions for MMP9 in kidney cysts formation and disease progression, we generated a mouse model by breeding juvenile cystic kidney (jck) mice with MMP9 deficient mice. Specifically, we provide evidence that MMP9 is overexpressed in cystic tissue where its enzymatic activity is increased 7-fold. MMP9 deficiency in cystic kidney worsen cystic kidney diseases by decreasing renal function, favoring cyst expansion and fibrosis. In addition, we find that periostin is a new critical substrate for MMP9 and in its absence periostin accumulates in cystic lining cells. As periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney diseases, we propose that the control of periostin by MMP9 and its associated intracellular signaling pathways including integrins, integrin-linked kinase and focal adhesion kinase confers to MMP9 a protective effect on the severity of the disease. [ABSTRACT FROM AUTHOR]

Published
2023
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6. IFT74variants cause skeletal ciliopathy and motile cilia defects in mice and humans

Author

Bakey, Zeineb, primary, Cabrera, Oscar A., additional, Hoefele, Julia, additional, Antony, Dinu, additional, Wu, Kaman, additional, Stuck, Michael W., additional, Micha, Dimitra, additional, Eguether, Thibaut, additional, Smith, Abigail O., additional, van der Wel, Nicole N., additional, Wagner, Matias, additional, Strittmatter, Lara, additional, Beales, Philip L., additional, Jonassen, Julie A., additional, Thiffault, Isabelle, additional, Cadieux-Dion, Maxime, additional, Boyes, Laura, additional, Sharif, Saba, additional, Tüysüz, Beyhan, additional, Dunstheimer, Desiree, additional, Niessen, Hans W.M., additional, Devine, William, additional, Lo, Cecilia W, additional, Mitchison, Hannah M., additional, Schmidts, Miriam, additional, and Pazour, Gregory J., additional

Published
2023
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7. Implication ofFOXD2dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT)

Author

Riedhammer, Korbinian M., Nguyen, Thanh-Minh T., Koşukcu, Can, Calzada-Wack, Julia, Li, Yong, Saygılı, Seha, Wimmers, Vera, Kim, Gwang-Jin, Chrysanthou, Marialena, Bakey, Zeineb, Kraiger, Markus, Sanz-Moreno, Adrián, Amarie, Oana V, Rathkolb, Birgit, Klein-Rodewald, Tanja, Garrett, Lillian, Hölter, Sabine M., Seisenberger, Claudia, Haug, Stefan, Marschall, Susan, Wurst, Wolfgang, Fuchs, Helmut, Gailus-Durner, Valerie, Wuttke, Matthias, Hrabe de Angelis, Martin, Ćomić, Jasmina, Akgün Doğan, Özlem, Özlük, Yasemin, Taşdemir, Mehmet, Ağbaş, Ayşe, Canpolat, Nur, Çalışkan, Salim, Weber, Ruthild, Bergmann, Carsten, Jeanpierre, Cecile, Saunier, Sophie, Lim, Tze Y., Hildebrandt, Friedhelm, Alhaddad, Bader, Wu, Kaman, Antony, Dinu, Matschkal, Julia, Schaaf, Christian, Renders, Lutz, Schmaderer, Christoph, Meitinger, Thomas, Heemann, Uwe, Köttgen, Anna, Arnold, Sebastian, Ozaltin, Fatih, Schmidts, Miriam, and Hoefele, Julia

Subjects
Article
Abstract

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below 30 years of age. Many monogenic forms have been discovered mainly due to comprehensive genetic testing like exome sequencing (ES). However, disease-causing variants in known disease-associated genes still only explain a proportion of cases. Aim of this study was to unravel the underlying molecular mechanism of syndromic CAKUT in two multiplex families with presumed autosomal recessive inheritance.Methods and ResultsES in the index individuals revealed two different rare homozygous variants inFOXD2,a transcription factor not previously implicated in CAKUT in humans: a frameshift in family 1 and a missense variant in family 2 with family segregation patterns consistent with autosomal-recessive inheritance. CRISPR/Cas9-derivedFoxd2knock-out (KO) mice presented with bilateral dilated renal pelvis accompanied by renal papilla atrophy while extrarenal features included mandibular, ophthalmologic, and behavioral anomalies, recapitulating the phenotype of humans withFOXD2dysfunction. To study the pathomechanism ofFOXD2-dysfunction-mediated developmental renal defects, in a complementary approach, we generated CRISPR/Cas9-mediated KO ofFoxd2in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important in renal/urogenital development, includingPax2andWnt4as well as gene expression changes indicating a cell identity shift towards a stromal cell identity. Histology ofFoxd2KO mouse kidneys confirmed increased fibrosis. Further, GWAS data (genome-wide association studies) suggests thatFOXD2could play a role for maintenance of podocyte integrity during adulthood.ConclusionsIn summary, our data implicate thatFOXD2dysfunction is a very rare cause of autosomal recessive syndromic CAKUT and suggest disturbances of the PAX2-WNT4 cell signaling axis contribute to this phenotype.

Published
2023
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9. Base editing derived models of human WDR34 and WDR60 disease alleles replicate retrograde IFT and hedgehog signaling defects and suggest disturbed Golgi protein transport

Author

Antony, Dinu, primary, Güleç, Elif Yýlmaz, additional, Bakey, Zeineb, additional, Schüle, Isabel, additional, Kim, Gwang-Jin, additional, Skatulla, Ilona, additional, Cathomen, Toni, additional, Brunner, Han, additional, Arnold, Sebastian, additional, and Schmidts, Miriam, additional

Published
2022
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10. Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases

Author

Antony, Dinu, primary, Gulec Yilmaz, Elif, additional, Gezdirici, Alper, additional, Slagter, Lennart, additional, Bakey, Zeineb, additional, Bornaun, Helen, additional, Tanidir, Ibrahim Cansaran, additional, Van Dinh, Tran, additional, Brunner, Han G., additional, Walentek, Peter, additional, Arnold, Sebastian J., additional, Backofen, Rolf, additional, and Schmidts, Miriam, additional

Published
2022
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11. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, cranio facial and genital features (COFG syndrome)

Author

Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Rad, Abolfazl; Altunoğlu, Umut; Miller, Rebecca; Maroofian, Reza; James, Kiely N.; Çağlayan, Ahmet Okay; Najafi, Maryam; Stanley, Valentina; Boustany, Rose-Mary; Yeşil, Gözde; Sahebzamani, Afsaneh; Ercan-Şençiçek, Gülhan; Saeidi, Kolsoum; Wu, Kaman; Bauer, Peter; Bakey, Zeineb; Gleeson, Joseph G.; Hauser, Natalie; Günel, Murat; Schmidts, Miriam, School of Medicine, Department of Medical Genetics, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Rad, Abolfazl; Altunoğlu, Umut; Miller, Rebecca; Maroofian, Reza; James, Kiely N.; Çağlayan, Ahmet Okay; Najafi, Maryam; Stanley, Valentina; Boustany, Rose-Mary; Yeşil, Gözde; Sahebzamani, Afsaneh; Ercan-Şençiçek, Gülhan; Saeidi, Kolsoum; Wu, Kaman; Bauer, Peter; Bakey, Zeineb; Gleeson, Joseph G.; Hauser, Natalie; Günel, Murat; Schmidts, Miriam, School of Medicine, and Department of Medical Genetics

Abstract

Background: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs. Objective: a homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families. Results: we identified four homozygous MAB21L1 loss of function variants (p.Glu281fs∗20, p.Arg287Glufs∗14 p.Tyr280∗ and p.Ser93Serfs∗48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly. Conclusion: this report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis., Simons Foundation for Autism Research; United States Department of Health & Human Services National Institutes of Health (NIH); Rady Children’s Institute for Genomic Medicine; Radboudumc; RIMLS Nijmegen (Hypatia tenure track fellowship); the ’Deutsche Forschungsgemeinschaft’ DFG; European Research Council (ERC StG TREATC ilia, grant No. 716344); European Union (European Union); H2020; ERAnet consortium CRANIRARE2; Yale Center for Mendelian Disorders; Gregory M. Kiez and Mehmet Kutman Foundation

Published
2019

13. Cover Image, Volume 40, Issue 3

Author

Rehman, Atteeq U., primary, Najafi, Maryam, additional, Kambouris, Marios, additional, Al-Gazali, Lihadh, additional, Makrythanasis, Periklis, additional, Rad, Abolfazl, additional, Maroofian, Reza, additional, Rajab, Anna, additional, Stark, Zornitza, additional, Hunter, Jill V., additional, Bakey, Zeineb, additional, Tokita, Mari J., additional, He, Weimin, additional, Vetrini, Francesco, additional, Petersen, Andrea, additional, Santoni, Federico A., additional, Hamamy, Hanan, additional, Wu, Kaman, additional, Al-Jasmi, Fatma, additional, Helmstädter, Martin, additional, Arnold, Sebastian J., additional, Xia, Fan, additional, Richmond, Christopher, additional, Liu, Pengfei, additional, Karimiani, Ehsan Ghayoor, additional, Karami Madani, GholamReza, additional, Lunke, Sebastian, additional, El-Shanti, Hatem, additional, Eng, Christine M., additional, Antonarakis, Stylianos E., additional, Hertecant, Jozef, additional, Walkiewicz, Magdalena, additional, Yang, Yaping, additional, and Schmidts, Miriam, additional

Published
2019
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14. Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Author

Rehman, Atteeq U., primary, Najafi, Maryam, additional, Kambouris, Marios, additional, Gazali, Lihadh Al, additional, Makrythanasis, Periklis, additional, Rad, Abolfazl, additional, Maroofian, Reza, additional, Rajab, Anna, additional, Stark, Zornitza, additional, Hunter, Jill V., additional, Bakey, Zeineb, additional, Tokita, Mari J., additional, He, Weimin, additional, Vetrini, Francesco, additional, Petersen, Andrea, additional, Santoni, Federico A., additional, Hamamy, Hanan, additional, Wu, Kaman, additional, Jasmi, Fatma Al, additional, Helmstädter, Martin, additional, Arnold, Sebastian J., additional, Xia, Fan, additional, Richmond, Christopher, additional, Liu, Pengfei, additional, Karimiani, Ehsan Ghayoor, additional, Madani, GholamReza Karami, additional, Lunke, Sebastian, additional, El‐Shanti, Hatem, additional, Eng, Christine M., additional, Antonarakis, Stylianos E., additional, Hertecant, Jozef, additional, Walkiewicz, Magdalena, additional, Yang, Yaping, additional, and Schmidts, Miriam, additional

Published
2018
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15. Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects

Author

Loges, Niki T., primary, Antony, Dinu, additional, Maver, Ales, additional, Deardorff, Matthew A., additional, Güleç, Elif Yýlmaz, additional, Gezdirici, Alper, additional, Nöthe-Menchen, Tabea, additional, Höben, Inga M., additional, Jelten, Lena, additional, Frank, Diana, additional, Werner, Claudius, additional, Tebbe, Johannes, additional, Wu, Kaman, additional, Goldmuntz, Elizabeth, additional, Čuturilo, Goran, additional, Krock, Bryan, additional, Ritter, Alyssa, additional, Hjeij, Rim, additional, Bakey, Zeineb, additional, Pennekamp, Petra, additional, Dworniczak, Bernd, additional, Brunner, Han, additional, Peterlin, Borut, additional, Tanidir, Cansaran, additional, Olbrich, Heike, additional, Omran, Heymut, additional, and Schmidts, Miriam, additional

Published
2018
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16. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctivecerebellar,ocular, craniofacial andgenital features (COFG syndrome)

Author

Rad, Abolfazl, primary, Altunoglu, Umut, additional, Miller, Rebecca, additional, Maroofian, Reza, additional, James, Kiely N, additional, Çağlayan, Ahmet Okay, additional, Najafi, Maryam, additional, Stanley, Valentina, additional, Boustany, Rose-Mary, additional, Yeşil, Gözde, additional, Sahebzamani, Afsaneh, additional, Ercan-Sencicek, Gülhan, additional, Saeidi, Kolsoum, additional, Wu, Kaman, additional, Bauer, Peter, additional, Bakey, Zeineb, additional, Gleeson, Joseph G, additional, Hauser, Natalie, additional, Gunel, Murat, additional, Kayserili, Hulya, additional, and Schmidts, Miriam, additional

Published
2018
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18. Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms

Author

Höben, Inga M., primary, Hjeij, Rim, additional, Olbrich, Heike, additional, Dougherty, Gerard W., additional, Nöthe-Menchen, Tabea, additional, Aprea, Isabella, additional, Frank, Diana, additional, Pennekamp, Petra, additional, Dworniczak, Bernd, additional, Wallmeier, Julia, additional, Raidt, Johanna, additional, Nielsen, Kim G., additional, Philipsen, Maria C., additional, Santamaria, Francesca, additional, Venditto, Laura, additional, Amirav, Israel, additional, Mussaffi, Huda, additional, Prenzel, Freerk, additional, Wu, Kaman, additional, Bakey, Zeineb, additional, Schmidts, Miriam, additional, Loges, Niki T., additional, and Omran, Heymut, additional

Published
2018
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20. Mutations in PIH1D3 Cause X-Linked Primary Ciliary Dyskinesia with Outer and Inner Dynein Arm Defects

Author

Paff, Tamara, primary, Loges, Niki T., additional, Aprea, Isabella, additional, Wu, Kaman, additional, Bakey, Zeineb, additional, Haarman, Eric G., additional, Daniels, Johannes M.A., additional, Sistermans, Erik A., additional, Bogunovic, Natalija, additional, Dougherty, Gerard W., additional, Höben, Inga M., additional, Große-Onnebrink, Jörg, additional, Matter, Anja, additional, Olbrich, Heike, additional, Werner, Claudius, additional, Pals, Gerard, additional, Schmidts, Miriam, additional, Omran, Heymut, additional, and Micha, Dimitra, additional

Published
2017
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21. The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes

Author

Bakey, Zeineb, Bihoreau, Marie-Thérèse, Piedagnel, Rémi, Delestré, Laure, Arnould, Catherine, de Villiers, Alexandre d'Hotman, Devuyst, Olivier, Hoffmann, Sigrid, Ronco, Pierre, Gauguier, Dominique, Lelongt, Brigitte, University of Zurich, and Lelongt, Brigitte

Subjects
2727 Nephrology, 570 Life sciences, biology, 610 Medicine & health, 10052 Institute of Physiology
Published
2015
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22. ANKS3 Co-Localises with ANKS6 in Mouse Renal Cilia and Is Associated with Vasopressin Signaling and Apoptosis In Vivo in Mice

Author

Delestré, Laure, Bakey, Zeineb, Prado, Cécilia, Hoffmann, Sigrid, Bihoreau, Marie-Thérèse, Lelongt, Brigitte, Gauguier, Dominique, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Heidelberg University Hospital [Heidelberg], National Genotyping Centre (CeGen), Human Cancer Genetics Programme, Spanish National Cancer Research Center (CNIO), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), INSERM UMR_S1155, CHU Tenon [APHP], CNIO, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and HAL UPMC, Gestionnaire

Subjects
Polycystic Kidney Diseases, [ SDV ] Life Sciences [q-bio], Vasopressins, [SDV]Life Sciences [q-bio], Amino Acid Motifs, lcsh:R, Down-Regulation, lcsh:Medicine, Apoptosis, Kidney, Ankyrin Repeat, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Mice, Mutation, Animals, lcsh:Q, Cilia, Carrier Proteins, lcsh:Science, Cell Proliferation, Protein Binding, Signal Transduction, Research Article
Abstract

International audience; Mutations in Ankyrin repeat and sterile alpha motif domain containing 6 (ANKS6) play a causative role in renal cyst formation in the PKD/Mhm(cy/+) rat model of polycystic kidney disease and in nephronophthisis in humans. A network of protein partners of ANKS6 is emerging and their functional characterization provides important clues to understand the role of ANKS6 in renal biology and in mechanisms involved in the formation of renal cysts. Following experimental confirmation of interaction between ANKS6and ANKS3 using a Yeast two hybrid system, we demonstrated that binding between the two proteins occurs through their sterile alpha motif (SAM) and that the amino acid 823 in rat ANSK6 is key for this interaction. We further showed their interaction by co-immunoprecipitation and showed in vivo in mice that ANKS3 is present in renal cilia. Downregulated expression of Anks3 in vivo in mice by Locked Nucleic Acid (LNA) modified antisense oligonucleotides was associated with increased transcription of vasopressin-induced genes, suggesting changes in renal water permeability, and altered transcription of genes encoding proteins involved in cilium structure, apoptosis and cell proliferation. These data provide experimental evidence of ANKS3-ANKS6 direct interaction through their SAM domain and co-localisation in mouse renal cilia, and shed light on molecular mechanisms indirectly mediated by ANKS6 in the mouse kidney, that may be affected by altered ANKS3-ANKS6 interaction. Our results contribute to improved knowledge of the structure and function of the network of proteins interacting with ANKS6, which may represent therapeutic targets in cystic diseases.

Published
2015
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23. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome).

Author

Rad, Abolfazl, Altunoglu, Umut, Miller, Rebecca, Maroofian, Reza, James, Kiely N., Çağlayan, Ahmet Okay, Najafi, Maryam, Stanley, Valentina, Boustany, Rose-Mary, Yeşil, Gözde, Sahebzamani, Afsaneh, Ercan-Sencicek, Gülhan, Saeidi, Kolsoum, Wu, Kaman, Bauer, Peter, Bakey, Zeineb, Gleeson, Joseph G., Hauser, Natalie, Gunel, Murat, and Kayserili, Hulya

Abstract

Background Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs. Objective A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families. Results We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly. Conclusion T his report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis. [ABSTRACT FROM AUTHOR]

Published
2019
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24. Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function.

Author

Rehman, Atteeq U., Najafi, Maryam, Kambouris, Marios, Al‐Gazali, Lihadh, Makrythanasis, Periklis, Rad, Abolfazl, Maroofian, Reza, Rajab, Anna, Stark, Zornitza, Hunter, Jill V., Bakey, Zeineb, Tokita, Mari J., He, Weimin, Vetrini, Francesco, Petersen, Andrea, Santoni, Federico A., Hamamy, Hanan, Wu, Kaman, Al‐Jasmi, Fatma, and Helmstädter, Martin

Abstract

Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway. We describe PPP1R21 loss of function in 4 independent families with syndromal neurodevelopmental delay by exome and genome sequencing. Immunoflorescence analysis reveals wildtype PPP1R21 localises to the early endosome and PPP1R21 loss of function in patient fibroblasts results in disturbances of the endosomal sorting process or endosome maturation pathway. [ABSTRACT FROM AUTHOR]

Published
2019
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25. The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes

Author

Bakey, Zeineb, primary, Bihoreau, Marie-Thérèse, additional, Piedagnel, Rémi, additional, Delestré, Laure, additional, Arnould, Catherine, additional, de Villiers, Alexandre d'Hotman, additional, Devuyst, Olivier, additional, Hoffmann, Sigrid, additional, Ronco, Pierre, additional, Gauguier, Dominique, additional, and Lelongt, Brigitte, additional

Published
2015
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26. Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140and confirms a Mainzer–Saldino syndrome diagnosis

Author

Oud, Machteld, Latour, Brooke, Bakey, Zeineb, Letteboer, Stef, Lugtenberg, Dorien, Wu, Ka, Cornelissen, Elisabeth, Yntema, Helger, Schmidts, Miriam, Roepman, Ronald, and Bongers, Ernie

Abstract

Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140,and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived Ift140knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. Diagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived Ift140knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer–Saldino syndrome, caused by variants in IFT140. We suggest the possibility that variants in IFT140may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing.

Published
2018
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27. Cellular ciliary phenotyping indicates pathogenicity of novel variants in <italic>IFT140</italic> and confirms a Mainzer–Saldino syndrome diagnosis.

Author

Oud, Machteld M., Latour, Brooke L., Bakey, Zeineb, Letteboer, Stef J., Lugtenberg, Dorien, Wu, Ka Man, Cornelissen, Elisabeth A. M., Yntema, Helger G., Schmidts, Miriam, Roepman, Ronald, and Bongers, Ernie M. H. F.

Subjects
SKELETAL abnormality diagnosis, CILIOPATHY, PHENOTYPES, EXOMES, MICROBIAL virulence
Abstract

Background: Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. Methods: We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived Ift140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. Results: Diagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived Ift140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. Conclusions: By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer–Saldino syndrome, caused by variants in IFT140. We suggest the possibility that variants in IFT140 may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing. [ABSTRACT FROM AUTHOR]

Published
2018
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28. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)

Author

Peter O. Bauer, Ahmet Okay Caglayan, Gülhan Ercan-Sencicek, Kolsoum Saeidi, Valentina Stanley, Joseph G. Gleeson, Maryam Najafi, Abolfazl Rad, Reza Maroofian, Kiely N. James, Hülya Kayserili, Rose-Mary Boustany, Zeineb Bakey, Murat Gunel, Natalie S. Hauser, Gozde Yesil, Rebecca Miller, Afsaneh Sahebzamani, Miriam Schmidts, Kaman Wu, Umut Altunoglu, YEŞİL, Gözde, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Rad, Abolfazl, Altunoğlu, Umut, Miller, Rebecca, Maroofian, Reza, James, Kiely N., Çağlayan, Ahmet Okay, Najafi, Maryam, Stanley, Valentina, Boustany, Rose-Mary, Yeşil, Gözde, Sahebzamani, Afsaneh, Ercan-Şençiçek, Gülhan, Saeidi, Kolsoum, Wu, Kaman, Bauer, Peter, Bakey, Zeineb, Gleeson, Joseph G., Hauser, Natalie, Günel, Murat, Schmidts, Miriam, School of Medicine, and Department of Medical Genetics

Subjects
0301 basic medicine, Male, Models, Molecular, Microcephaly, Pathology, Protein Conformation, 030105 genetics & heredity, Consanguinity, Neurodevelopmental disorder, Loss of Function Mutation, Child, Cerebellar hypoplasia, Genetics (clinical), Exome sequencing, Developmental Defects, Homozygote, Brain, Syndrome, Disease gene identification, Magnetic Resonance Imaging, Pedigree, Phenotype, Agenesis, Cerebello-Oculo-Facio-genital (COFG) syndrome, Child, Preschool, Female, medicine.symptom, medicine.medical_specialty, Ataxia, corneal dystrophy, Pontocerebellar hypoplasia, Polymorphism, Single Nucleotide, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Exome Sequencing, Rad A., Altunoglu U., Miller R., Maroofian R., James K. N. , Caglayan A. O. , Najafi M., Stanley V., Boustany R., YEŞİL G., et al., -MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome)-, JOURNAL OF MEDICAL GENETICS, cilt.56, ss.332-339, 2019, Genetics, medicine, scrotal/labial aplasia, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Genetic Association Studies, MAB21L1, Homeodomain Proteins, Medicine, Genetics and heredity, business.industry, pontocerebellar hypoplasia, Facies, Infant, medicine.disease, Corneal dystrophy, Scrotal/labial aplasia, 030104 developmental biology, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Neurodevelopmental Disorders, business
Abstract

Background: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs. Objective: a homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families. Results: we identified four homozygous MAB21L1 loss of function variants (p.Glu281fs∗20, p.Arg287Glufs∗14 p.Tyr280∗ and p.Ser93Serfs∗48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly. Conclusion: this report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis., Simons Foundation for Autism Research; United States Department of Health & Human Services National Institutes of Health (NIH); Rady Children’s Institute for Genomic Medicine; Radboudumc; RIMLS Nijmegen (Hypatia tenure track fellowship); the ’Deutsche Forschungsgemeinschaft’ DFG; European Research Council (ERC StG TREATC ilia, grant No. 716344); European Union (European Union); H2020; ERAnet consortium CRANIRARE2; Yale Center for Mendelian Disorders; Gregory M. Kiez and Mehmet Kutman Foundation

Published
2019

29. Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms

Author

Gerard W. Dougherty, Petra Pennekamp, Johanna Raidt, Inga M. Höben, Laura Venditto, Julia Wallmeier, Israel Amirav, Tabea Nöthe-Menchen, Heymut Omran, Diana Frank, Huda Mussaffi, Kaman Wu, Kim G. Nielsen, Niki T. Loges, Maria C. Philipsen, Bernd Dworniczak, Zeineb Bakey, Isabella Aprea, Francesca Santamaria, Miriam Schmidts, Freerk Prenzel, Rim Hjeij, Heike Olbrich, Höben, Inga M., Hjeij, Rim, Olbrich, Heike, Dougherty, Gerard W., Nöthe-Menchen, Tabea, Aprea, Isabella, Frank, Diana, Pennekamp, Petra, Dworniczak, Bernd, Wallmeier, Julia, Raidt, Johanna, Nielsen, Kim G., Philipsen, Maria C., Santamaria, Francesca, Venditto, Laura, Amirav, Israel, Mussaffi, Huda, Prenzel, Freerk, Wu, Kaman, Bakey, Zeineb, Schmidts, Miriam, Loges, Niki T., and Omran, Heymut

Subjects
Male, 0301 basic medicine, primary ciliary dyskinesia, Genes, Recessive, Flagellum, Biology, Male infertility, Pathogenesis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, dynein arm, Genetic, Loss of Function Mutation, Report, Ciliogenesis, preassembly, Genetics, medicine, Humans, Genetics (clinical), Nuclear Protein, Body Patterning, Primary ciliary dyskinesia, Kartagener Syndrome, Cilium, cilia, Dynein, Dyneins, Nuclear Proteins, C11ORF70, medicine.disease, Sperm, sperm flagella, 3. Good health, Cell biology, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Sperm Tail, Mutation, Motile cilium, Female, Human
Abstract

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11orf70 showed that C11orf70 is expressed in ciliated respiratory cells and that the expression of C11orf70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein-arm assembly factors. Furthermore, C11orf70 shows an interaction with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11orf70 is a preassembly factor involved in the pathogenesis of PCD. The identification of additional genetic defects that cause PCD and male infertility is of great importance for the clinic as well as for genetic counselling.

Published
2018
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30. IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.

Author

Bakey Z, Cabrera OA, Hoefele J, Antony D, Wu K, Stuck MW, Micha D, Eguether T, Smith AO, van der Wel NN, Wagner M, Strittmatter L, Beales PL, Jonassen JA, Thiffault I, Cadieux-Dion M, Boyes L, Sharif S, Tüysüz B, Dunstheimer D, Niessen HWM, Devine W, Lo CW, Mitchison HM, Schmidts M, and Pazour GJ

Abstract

Motile and non-motile cilia are critical to mammalian development and health. Assembly of these organelles depends on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). A series of human and mouse IFT74 variants were studied to understand the function of this IFT subunit. Humans missing exon 2, which codes for the first 40 residues, presented an unusual combination of ciliary chondrodysplasia and mucociliary clearance disorders while individuals carrying biallelic splice site variants developed a lethal skeletal chondrodysplasia. In mice, variants thought to remove all Ift74 function, completely block ciliary assembly and result in midgestational lethality. A mouse allele that removes the first 40 amino acids, analogous to the human exon 2 deletion, results in a motile cilia phenotype with mild skeletal abnormalities. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia could account for the motile cilia phenotype observed in human and mice.

Published
2023
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31. MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive c erebellar, o cular, cranio f acial and g enital features (COFG syndrome).

Author

Rad A, Altunoglu U, Miller R, Maroofian R, James KN, Çağlayan AO, Najafi M, Stanley V, Boustany RM, Yeşil G, Sahebzamani A, Ercan-Sencicek G, Saeidi K, Wu K, Bauer P, Bakey Z, Gleeson JG, Hauser N, Gunel M, Kayserili H, and Schmidts M

Subjects
Brain abnormalities, Brain diagnostic imaging, Child, Child, Preschool, Consanguinity, Facies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Homeodomain Proteins chemistry, Homozygote, Humans, Infant, Magnetic Resonance Imaging, Male, Models, Molecular, Pedigree, Polymorphism, Single Nucleotide, Protein Conformation, Syndrome, Exome Sequencing, Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Homeodomain Proteins genetics, Loss of Function Mutation, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics, Phenotype
Abstract

Background: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs., Objective: A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families., Results: We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly., Conclusion: This report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Published
2019
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