Portal de Periódicos da CAPES

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss

2021; Elsevier BV; Volume: 108; Issue: 10 Linguagem: Inglês

10.1016/j.ajhg.2021.08.003

1537-6605

Élodie M. Richard, Somayeh Bakhtiari, Ashley P.L. Marsh, Rauan Kaiyrzhanov, Matias Wagner, Sheetal Shetty, Alex M. Pagnozzi, Sandra M. Nordlie, Brandon S. Guida, Patricia Cornejo, Helen Magee, James Liu, Bethany Y. Norton, Richard Webster, Lisa Worgan, Hákon Hákonarson, Jiankang Li, Yiran Guo, Mahim Jain, Alyssa Blesson, Lance H. Rodan, Mary-Alice Abbott, Anne M. Comi, Julie S. Cohen, Bader Alhaddad, Thomas Meitinger, Dominic Lenz, Andreas Ziegler, Urania Kotzaeridou, Theresa Brunet, Anna Chassevent, Constance Smith‐Hicks, Joseph Ekstein, Tzvi Weiden, Andreas Hahn, Nazira Zharkinbekova, Peter D. Turnpenny, Arianna Tucci, Melissa Yelton, Rita Horváth, Serdal Güngör, Semra Hız, Yavuz Oktay, Hanns Lochmüller, Marcella Zollino, Manuela Morleo, Giuseppe Marangi, Vincenzo Nigro, Annalaura Torella, Michele Pinelli, Simona Amenta, Ralf A. Husain, Benita Großmann, Marion Rapp, Claudia Steen, Iris Marquardt, Mona Grimmel, Ute Grasshoff, G. Christoph Korenke, Marta Owczarek‐Lipska, John Neidhardt, Francesca Clementina Radio, Cecilia Mancini, Dianela Judith Claps Sepulveda, Kirsty McWalter, Amber Begtrup, Amy Crunk, María J. Guillen Sacoto, Richard Person, Rhonda E. Schnur, Maria Margherita Mancardi, Florian Kreuder, Pasquale Striano, Federico Zara, Wendy K. Chung, Warren A. Marks, Clare L. van Eyk, Dani L. Webber, Mark Corbett, Kelly Harper, Jesia G. Berry, Alastair H. MacLennan, Jozef Gécz, Marco Tartaglia, Vincenzo Salpietro, John Christodoulou, Jan Kaslin, Sergio Padilla-López, Kaya Bilgüvar, Alexander Münchau, Zubair M. Ahmed, Robert B. Hufnagel, Michael Fahey, Reza Maroofian, Henry Houlden, Heinrich Sticht, Shrikant Mane, Abolfazl Rad, Barbara Vona, Sheng Chih Jin, Tobias B. Haack, Christine Makowski, Yoel Hirsch, Saima Riazuddin, Michael C. Kruer,

Mitochondrial Function and Pathology

Summary Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.