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1. Infantile SOD1 deficiency syndrome caused by a homozygous SOD1 variant with absence of enzyme activity

Author

Ezer, Shlomit, Daana, Muhannad, Park, Julien H., Yanovsky-Dagan, Shira, Nordström, Ulrika, Basal, Adily, Edvardson, Simon, Saada, Ann, Otto, Markus, Meiner, Vardiella, Marklund, Stefan L., Andersen, Peter Munch, Harel, Tamar, Ezer, Shlomit, Daana, Muhannad, Park, Julien H., Yanovsky-Dagan, Shira, Nordström, Ulrika, Basal, Adily, Edvardson, Simon, Saada, Ann, Otto, Markus, Meiner, Vardiella, Marklund, Stefan L., Andersen, Peter Munch, and Harel, Tamar

Abstract

Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.

Published
2022
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2. RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1

Author

Abu-Libdeh, Bassam, Jhujh, Satpal S, Dhar, Srijita, Sommers, Joshua A, Datta, Arindam, Longo, Gabriel M C, Grange, Laura J, Reynolds, John J, Cooke, Sophie L, McNee, Gavin S, Hollingworth, Robert, Woodward, Beth L, Ganesh, Anil N, Smerdon, Stephen J, Nicolae, Claudia M, Durlacher-Betzer, Karina, Molho-Pessach, Vered, Abu-Libdeh, Abdulsalam, Meiner, Vardiella, Moldovan, George-Lucian, Roukos, Vassilis, Harel, Tamar, Brosh, Robert M, Stewart, Grant S, Abu-Libdeh, Bassam, Jhujh, Satpal S, Dhar, Srijita, Sommers, Joshua A, Datta, Arindam, Longo, Gabriel M C, Grange, Laura J, Reynolds, John J, Cooke, Sophie L, McNee, Gavin S, Hollingworth, Robert, Woodward, Beth L, Ganesh, Anil N, Smerdon, Stephen J, Nicolae, Claudia M, Durlacher-Betzer, Karina, Molho-Pessach, Vered, Abu-Libdeh, Abdulsalam, Meiner, Vardiella, Moldovan, George-Lucian, Roukos, Vassilis, Harel, Tamar, Brosh, Robert M, and Stewart, Grant S

Abstract

Despite being the first homolog of the bacterial RecQ helicase to be identified in humans, the function of RECQL1 remains poorly characterized. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here, we identify 2 families with a genome instability disorder that we have named RECON (RECql ONe) syndrome, caused by biallelic mutations in the RECQL gene. The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity and were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser), located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase, and fork restoration activity, while its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.

Published
2022

3. RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1

Author

Abu-Libdeh, Bassam, Jhujh, Satpal S, Dhar, Srijita, Sommers, Joshua A, Datta, Arindam, Longo, Gabriel M C, Grange, Laura J, Reynolds, John J, Cooke, Sophie L, McNee, Gavin S, Hollingworth, Robert, Woodward, Beth L, Ganesh, Anil N, Smerdon, Stephen J, Nicolae, Claudia M, Durlacher-Betzer, Karina, Molho-Pessach, Vered, Abu-Libdeh, Abdulsalam, Meiner, Vardiella, Moldovan, George-Lucian, Roukos, Vassilis, Harel, Tamar, Brosh, Robert M, Stewart, Grant S, Abu-Libdeh, Bassam, Jhujh, Satpal S, Dhar, Srijita, Sommers, Joshua A, Datta, Arindam, Longo, Gabriel M C, Grange, Laura J, Reynolds, John J, Cooke, Sophie L, McNee, Gavin S, Hollingworth, Robert, Woodward, Beth L, Ganesh, Anil N, Smerdon, Stephen J, Nicolae, Claudia M, Durlacher-Betzer, Karina, Molho-Pessach, Vered, Abu-Libdeh, Abdulsalam, Meiner, Vardiella, Moldovan, George-Lucian, Roukos, Vassilis, Harel, Tamar, Brosh, Robert M, and Stewart, Grant S

Abstract

Despite being the first homolog of the bacterial RecQ helicase to be identified in humans, the function of RECQL1 remains poorly characterized. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here, we identify 2 families with a genome instability disorder that we have named RECON (RECql ONe) syndrome, caused by biallelic mutations in the RECQL gene. The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity and were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser), located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase, and fork restoration activity, while its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.

Published
2022

4. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Author

den Hoed, Joery, den Hoed, Joery, de Boer, Elke, Voisin, Norine, Dingemans, Alexander, Guex, Nicolas, Wiel, Laurens, Nellaker, Christoffer, Amudhavalli, Shivarajan, Banka, Siddharth, Bena, Frederique, Ben-Zeev, Bruria, Bonagura, Vincent, Bruel, Ange-Line, Brunet, Theresa, Brunner, Han, Chew, Hui, Chrast, Jacqueline, Cimbalistienė, Loreta, Coon, Hilary, Délot, Emmanuèlle, Démurger, Florence, Denommé-Pichon, Anne-Sophie, Depienne, Christel, Donnai, Dian, Dyment, David, Elpeleg, Orly, Faivre, Laurence, Gilissen, Christian, Granger, Leslie, Haber, Benjamin, Hachiya, Yasuo, Abedi, Yasmin, Hanebeck, Jennifer, Hehir-Kwa, Jayne, Horist, Brooke, Itai, Toshiyuki, Jackson, Adam, Jewell, Rosalyn, Jones, Kelly, Joss, Shelagh, Kashii, Hirofumi, Kato, Mitsuhiro, Kattentidt-Mouravieva, Anja, Kok, Fernando, Kotzaeridou, Urania, Krishnamurthy, Vidya, Kučinskas, Vaidutis, Kuechler, Alma, Lavillaureix, Alinoë, Liu, Pengfei, Manwaring, Linda, Matsumoto, Naomichi, Mazel, Benoît, McWalter, Kirsty, Meiner, Vardiella, Mikati, Mohamad, Miyatake, Satoko, Mizuguchi, Takeshi, Moey, Lip, Mohammed, Shehla, Mor-Shaked, Hagar, Mountford, Hayley, Newbury-Ecob, Ruth, Odent, Sylvie, Orec, Laura, Osmond, Matthew, Palculict, Timothy, Parker, Michael, Petersen, Andrea, Pfundt, Rolph, Preikšaitienė, Eglė, Radtke, Kelly, Ranza, Emmanuelle, Rosenfeld, Jill, Santiago-Sim, Teresa, Schwager, Caitlin, Sinnema, Margje, Snijders Blok, Lot, Spillmann, Rebecca, Stegmann, Alexander, Thiffault, Isabelle, Tran, Linh, Vaknin-Dembinsky, Adi, Vedovato-Dos-Santos, Juliana, Schrier Vergano, Samantha, Vilain, Eric, Vitobello, Antonio, Wagner, Matias, Waheeb, Androu, Willing, Marcia, Zuccarelli, Britton, Kini, Usha, Newbury, Dianne, Kleefstra, Tjitske, Reymond, Alexandre, Fisher, Simon, Vissers, Lisenka, den Hoed, Joery, den Hoed, Joery, de Boer, Elke, Voisin, Norine, Dingemans, Alexander, Guex, Nicolas, Wiel, Laurens, Nellaker, Christoffer, Amudhavalli, Shivarajan, Banka, Siddharth, Bena, Frederique, Ben-Zeev, Bruria, Bonagura, Vincent, Bruel, Ange-Line, Brunet, Theresa, Brunner, Han, Chew, Hui, Chrast, Jacqueline, Cimbalistienė, Loreta, Coon, Hilary, Délot, Emmanuèlle, Démurger, Florence, Denommé-Pichon, Anne-Sophie, Depienne, Christel, Donnai, Dian, Dyment, David, Elpeleg, Orly, Faivre, Laurence, Gilissen, Christian, Granger, Leslie, Haber, Benjamin, Hachiya, Yasuo, Abedi, Yasmin, Hanebeck, Jennifer, Hehir-Kwa, Jayne, Horist, Brooke, Itai, Toshiyuki, Jackson, Adam, Jewell, Rosalyn, Jones, Kelly, Joss, Shelagh, Kashii, Hirofumi, Kato, Mitsuhiro, Kattentidt-Mouravieva, Anja, Kok, Fernando, Kotzaeridou, Urania, Krishnamurthy, Vidya, Kučinskas, Vaidutis, Kuechler, Alma, Lavillaureix, Alinoë, Liu, Pengfei, Manwaring, Linda, Matsumoto, Naomichi, Mazel, Benoît, McWalter, Kirsty, Meiner, Vardiella, Mikati, Mohamad, Miyatake, Satoko, Mizuguchi, Takeshi, Moey, Lip, Mohammed, Shehla, Mor-Shaked, Hagar, Mountford, Hayley, Newbury-Ecob, Ruth, Odent, Sylvie, Orec, Laura, Osmond, Matthew, Palculict, Timothy, Parker, Michael, Petersen, Andrea, Pfundt, Rolph, Preikšaitienė, Eglė, Radtke, Kelly, Ranza, Emmanuelle, Rosenfeld, Jill, Santiago-Sim, Teresa, Schwager, Caitlin, Sinnema, Margje, Snijders Blok, Lot, Spillmann, Rebecca, Stegmann, Alexander, Thiffault, Isabelle, Tran, Linh, Vaknin-Dembinsky, Adi, Vedovato-Dos-Santos, Juliana, Schrier Vergano, Samantha, Vilain, Eric, Vitobello, Antonio, Wagner, Matias, Waheeb, Androu, Willing, Marcia, Zuccarelli, Britton, Kini, Usha, Newbury, Dianne, Kleefstra, Tjitske, Reymond, Alexandre, Fisher, Simon, and Vissers, Lisenka

Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Published
2021

5. Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

Author

Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex, V, Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., Sefiani, Abdelaziz, Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex, V, Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., and Sefiani, Abdelaziz

Abstract

A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fatla mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic fissure fusion during vertebrate eye development. Our findings establish FAT1 as a gene with pleiotropic effects in human, in that frameshift mutations cause a severe multi-system disorder whereas recessive missense mutations had been previously associated with isolated glomerulotubular nephropathy.

Published
2019

6. Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

Author

Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex, V, Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., Sefiani, Abdelaziz, Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex, V, Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., and Sefiani, Abdelaziz

Abstract

A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fatla mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic fissure fusion during vertebrate eye development. Our findings establish FAT1 as a gene with pleiotropic effects in human, in that frameshift mutations cause a severe multi-system disorder whereas recessive missense mutations had been previously associated with isolated glomerulotubular nephropathy.

Published
2019

7. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder

Author

Lossos, Alexander, Elazar, Nimrod, Lerer, Israela, Schueler-Furman, Ora, Fellig, Yakov, Glick, Benjamin, Zimmerman, Bat-El, Azulay, Haim, Dotan, Shlomo, Goldberg, Sharon, Gomori, John M., Ponger, Penina, Newman, J. P., Marreed, Hodaifah, Steck, Andreas J., Schaeren-Wiemers, Nicole, Mor, Nofar, Harel, Michal, Geiger, Tamar, Eshed-Eisenbach, Yael, Meiner, Vardiella, Peles, Elior, Lossos, Alexander, Elazar, Nimrod, Lerer, Israela, Schueler-Furman, Ora, Fellig, Yakov, Glick, Benjamin, Zimmerman, Bat-El, Azulay, Haim, Dotan, Shlomo, Goldberg, Sharon, Gomori, John M., Ponger, Penina, Newman, J. P., Marreed, Hodaifah, Steck, Andreas J., Schaeren-Wiemers, Nicole, Mor, Nofar, Harel, Michal, Geiger, Tamar, Eshed-Eisenbach, Yael, Meiner, Vardiella, and Peles, Elior

Abstract

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy. Lossos et al. describe a family with an early-onset Pelizaeus-Merzbacher disease-like phenotype that slowly evolves into complicated hereditary spastic paraplegia, affecting both the CNS and PNS. Exome sequencing reveals a causative homozygous missense mutation in MAG, which encodes myelin associated glycoprotein

Published
2017

9. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder

Author

Lossos, Alexander, Elazar, Nimrod, Lerer, Israela, Schueler-Furman, Ora, Fellig, Yakov, Glick, Benjamin, Zimmerman, Bat-El, Azulay, Haim, Dotan, Shlomo, Goldberg, Sharon, Gomori, John M., Ponger, Penina, Newman, J. P., Marreed, Hodaifah, Steck, Andreas J., Schaeren-Wiemers, Nicole, Mor, Nofar, Harel, Michal, Geiger, Tamar, Eshed-Eisenbach, Yael, Meiner, Vardiella, Peles, Elior, Lossos, Alexander, Elazar, Nimrod, Lerer, Israela, Schueler-Furman, Ora, Fellig, Yakov, Glick, Benjamin, Zimmerman, Bat-El, Azulay, Haim, Dotan, Shlomo, Goldberg, Sharon, Gomori, John M., Ponger, Penina, Newman, J. P., Marreed, Hodaifah, Steck, Andreas J., Schaeren-Wiemers, Nicole, Mor, Nofar, Harel, Michal, Geiger, Tamar, Eshed-Eisenbach, Yael, Meiner, Vardiella, and Peles, Elior

Abstract

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy. Lossos et al. describe a family with an early-onset Pelizaeus-Merzbacher disease-like phenotype that slowly evolves into complicated hereditary spastic paraplegia, affecting both the CNS and PNS. Exome sequencing reveals a causative homozygous missense mutation in MAG, which encodes myelin associated glycoprotein

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