von Ulrike Mütze ; Lucy Henze ; Florian Gleich ; Martin Lindner ; Sarah C. Grünert ; Ute Spiekerkoetter ; René Santer ; Holger Blessing ; Eva Thimm ; Regina Ensenauer ; Johannes Weigel ; Skadi Beblo ; Maria Arélin ; Julia B. Hennermann ; Thorsten Marquardt ; Iris Marquardt ; Peter Freisinger ; Johannes Krämer ; Andrea Dieckmann ; Natalie Weinhold ; Mareike Keller ; Magdalena Walter ; Katharina A. Schiergens ; Esther M. Maier ; Georg F. Hoffmann ; Sven F. Garbade ; Stefan Kölker
von Elodie M. Richard ; Somayeh Bakhtiari ; Ashley P. L. Marsh ; Rauan Kaiyrzhanov ; Matias Wagner ; Sheetal Shetty ; Alex Pagnozzi ; Sandra M. Nordlie ; Brandon S. Guida ; Patricia Cornejo ; Helen Magee ; James Liu ; Bethany Y. Norton ; Richard I. Webster ; Lisa Worgan ; Hakon Hakonarson ; Jiankang Li ; Yiran Guo ; Mahim Jain ; Alyssa Blesson ; Lance H. Rodan ; Mary-Alice Abbott ; Anne 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 Turnpenny ; Arianna Tucci ; Melissa Yelton ; Rita Horvath ; Serdal Gungor ; Semra Hiz ; Yavuz Oktay ; Hanns Lochmuller ; 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 ; Christoph Korenke ; Marta Owczarek-Lipska ; John Neidhardt ; Francesca Clementina Radio ; Cecilia Mancini ; Dianela Judith Claps Sepulveda ; Kirsty McWalter ; Amber Begtrup ; Amy Crunk ; Maria 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 A. Corbett ; Kelly Harper ; Jesia G. Berry ; Alastair H. MacLennan ; Jozef Gecz ; Marco Tartaglia ; Vincenzo Salpietro ; John Christodoulou ; Jan Kaslin ; Sergio Padilla-Lopez ; Kaya Bilguvar ; Alexander Munchau ; Zubair M. Ahmed ; Robert B. Hufnagel ; Michael C. Fahey ; Reza Maroofian ; Henry Houlden ; Heinrich Sticht ; Shrikant M. Mane ; Aboulfazl Rad ; Barbara Vona ; Sheng Chih Jin ; Tobias B. Haack ; Christine Makowski ; Yoel Hirsch ; Saima Riazuddin ; Michael C. Kruer
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.
The American journal of human genetics New York, NY [u.a.] : Cell Press, 1949 108(2021), 10, Seite 2006-2016
von Pauline E. Schneeberger ; Leonie von Elsner ; Emma L. Barker ; Peter Meinecke ; Iris Marquardt ; Malik Alawi ; Katharina Steindl ; Pascal Joset ; Anita Rauch ; Petra J.G. Zwijnenburg ; Marjan M. Weiss ; Catherine L.R. Merry ; Kerstin Kutsche
Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals’ fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.
The American journal of human genetics New York, NY [u.a.] : Cell Press, 1949 101(2017), 2, Seite 283-290
