De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Manole, Andreea; Efthymiou, Stéphanie; O’Connor, Emer; Mendes, Marisa I.; Jennings, Matthew J.; Maroofian, Reza; Davagnanam, Indran; Mankad, Kshitij; López, María Rodríguez; Salpietro, Vincenzo; Harripaul, Ricardo; Badalato, Lauren; Walia, Jagdeep S.; Francklyn, Christopher S.; Athanasiou-Fragkouli, Alkyoni; Sullivan, Roisin; Desai, Sonal; Barañano, Kristin W.; Zafar, Faisal; Rana, Nuzhat; Ilyas, Muhammad; Horga, A; Kara, Majdi; Mattioli, Francesca; Goldenberg, Alice; Griffin, Helen; Piton, Amélie; Henderson, Lindsay B.; Kara, Benyekhlef; Aslanger, Ayça Dilruba; Raaphorst, Joost; Pfundt, Rolph; Portier, R; Shinawi, Marwan; Kirby, Amelia; Christensen, Katherine; Wang, Lu; Rosti, Rasim Özgür; Paracha, Sohail Aziz; Sarwar, Muhammad Tahir; Jenkins, Dagan; Ahmed, Jawad; Santoni, Federico; Ranza, Emmanuelle; Iwaszkiewicz, Justyna; Cytrynbaum, Cheryl; Weksberg, Rosanna; Wentzensen, Ingrid M.; Sacoto, María J. Guillen; Si, Yue; Telegrafi, Aida; Andrews, Marisa V.; Baldridge, Dustin; Gabriel, Heinz; Mohr, Julia; Oehl-Jaschkowitz, Barbara; Debard, Sylvain; Senger, Bruno; Fischer, Frédéric; Ravenwaaij, Conny van; Fock, Annemarie; Stevens, Servi J.C.; Bähler, Jürg; Nasar, Amina; Mantovani, John F.; Manzur, Adnan; Sárközy, Anna; Smith, Desirée E.C.; Salomons, Gajja S.; Ahmed, Zubair M.; Riazuddin, S.; Riazuddin, Saima; Usmani, Muhammad A.; Seibt, Annette; Ansar, Muhammad; Antonarakis, Stylianos E.; Vincent, John B.; Ayub, Muhammad; Grimmel, Mona; Jelsig, Anne Marie; Hjortshøj, Tina Duelund; Karstensen, Helena Gásdal; Hummel, Marybeth; Haack, Tobias B.; Jamshidi, Yalda; Distelmaier, Felix; Horvath, Rita; Gleeson, Joseph G.; Becker, Hubert Dominique; Mandel, Jean Louis; Koolen, David A.; Houlden, Henry

doi:10.1016/j.ajhg.2020.06.016

Cited by 35 publications

(20 citation statements)

References 44 publications

(77 reference statements)

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“…Of note, an association between de novo loss-of-function variants in KIF17 and neurodevelopmental phenotypes, including abnormal behavior and schizophrenia, was previously proposed [ 18 ]. Different genes encoding kinesins and motor proteins have been previously implicated in brain development, and defining the full spectrum of disease-causing molecular pathways will help to diagnose, monitor, and accelerate treatment development in genetic neurodevelopmental conditions with associated cytoskeleton alterations or modulating ionotropic glutamate receptor subunits [ 19 , 20 , 21 , 22 , 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Biallelic Variants in KIF17 Associated with Microphthalmia and Coloboma Spectrum

Riva

Gambadauro

Dipasquale

et al. 2021

IJMS

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Microphthalmia, anophthalmia, and coloboma (MAC) are a group of congenital eye anomalies that can affect one or both eyes. Patients can present one or a combination of these ocular abnormalities in the so called “MAC spectrum”. The KIF17 gene encodes the kinesin-like protein Kif17, a microtubule-based, ATP-dependent, motor protein that is pivotal for outer segment development and disc morphogenesis in different animal models, including mice and zebrafish. In this report, we describe a Sicilian family with two siblings affected with congenital coloboma, microphthalmia, and a mild delay of motor developmental milestones. Genomic DNA from the siblings and their unaffected parents was sequenced with a clinical exome that revealed compound heterozygous variants in the KIF17 gene (NM_020816.4: c.1255C > T (p.Arg419Trp); c.2554C > T (p.Arg852Cys)) segregating with the MAC spectrum phenotype of the two affected siblings. Variants were inherited from the healthy mother and father, are present at a very low-frequency in genomic population databases, and are predicted to be deleterious in silico. Our report indicates the potential co-segregation of these biallelic KIF17 variants with microphthalmia and coloboma, highlighting a potential conserved role of this gene in eye development across different species.

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Section: Discussionmentioning

confidence: 99%

Biallelic Variants in KIF17 Associated with Microphthalmia and Coloboma Spectrum

Riva

Gambadauro

Dipasquale

et al. 2021

IJMS

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“…For example, biallelic NARS variants were identified in 7 affected patients with recessive microcephaly from three unrelated families (Wang et al., 2020). Another study described de novo dominant heterozygous and biallelic recessive variants in the NARS in 32 individuals from 21 families, presenting with multiple neurodevelopmental defects (Manole et al., 2020). Interestingly, functional data indicated that genotypes with dominant heterozygous NARS variants produce a toxic gain‐of‐function, whereas the homozygous recessive variants probably induce a partial loss of function (Manole et al., 2020; Wang et al., 2020).…”

Section: Other Putative Neuropathy‐associated Variantsmentioning

confidence: 99%

“…Another study described de novo dominant heterozygous and biallelic recessive variants in the NARS in 32 individuals from 21 families, presenting with multiple neurodevelopmental defects (Manole et al., 2020). Interestingly, functional data indicated that genotypes with dominant heterozygous NARS variants produce a toxic gain‐of‐function, whereas the homozygous recessive variants probably induce a partial loss of function (Manole et al., 2020; Wang et al., 2020). Although neuropathies other than CMT are outside the scope of this review, these studies do shed light on the complex pathogenic mechanisms of aaRSs in neuropathies.…”

Section: Other Putative Neuropathy‐associated Variantsmentioning

confidence: 99%

Aminoacyl‐tRNA synthetases in Charcot–Marie–Tooth disease: A gain or a loss?

Zhang

Zhou

Sun

2020

Journal of Neurochemistry

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Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurodegenerative disorders with an increasing number of CMT-associated variants identified as causative factors, however, there has been no effective therapy for CMT to date. Aminoacyl-tRNA synthetases (aaRS) are essential enzymes in translation by charging amino acids onto their cognate tRNAs during protein synthesis. Dominant monoallelic variants of aaRSs have been largely implicated in CMT. Some aaRSs variants affect enzymatic activity, demonstrating a loss-of-function property. In contrast, loss of aminoacylation activity is neither necessary nor sufficient for some aaRSs variants to cause CMT. Instead, accumulating evidence from CMT patient samples, animal genetic studies or protein conformational analysis has pinpointed toxic gainof-function of aaRSs variants in CMT, suggesting complicated mechanisms underlying the pathogenesis of CMT. In this review, we summarize the latest advances in studies on CMT-linked aaRSs, with a particular focus on their functions. The current challenges, future direction and the promising candidates for potential treatment of CMT are also discussed. K E Y W O R D Saminoacyl-tRNA synthetases, animal model, charcot-marie-tooth disease, mutation, pathogenesis This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…Despite being in the era of next-generation sequencing (NGS), the etiology and disease mechanisms underlying regressive neurodevelopmental impairment remain undetermined in a certain proportion of cases [ 4 , 5 ]. Defining the full spectrum of disease-causing molecular pathways underlying neurodevelopmental disorders will help to diagnose and monitor developmental trajectories in children affected with these conditions [ 6 , 7 , 8 , 9 , 10 , 11 ]…”

Section: Introductionmentioning

confidence: 99%

Prominent and Regressive Brain Developmental Disorders Associated with Nance-Horan Syndrome

et al. 2021

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Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder caused mainly by loss of function variants in the NHS gene. NHS is characterized by congenital cataracts, dental anomalies, and distinctive facial features, and a proportion of the affected individuals also present intellectual disability and congenital cardiopathies. Despite identification of at least 40 distinct hemizygous variants leading to NHS, genotype-phenotype correlations remain largely elusive. In this study, we describe a Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing (WES). The affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies. Furthermore, brain imaging showed corpus callosum anomalies and periventricular leukoencephalopathy. We expand the phenotypic and mutational NHS spectrum and review potential disease mechanisms underlying the central neurological anomalies and the potential neurodevelopmental features associated with NHS.

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De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Cited by 35 publications

References 44 publications

Biallelic Variants in KIF17 Associated with Microphthalmia and Coloboma Spectrum

Biallelic Variants in KIF17 Associated with Microphthalmia and Coloboma Spectrum

Aminoacyl‐tRNA synthetases in Charcot–Marie–Tooth disease: A gain or a loss?

Prominent and Regressive Brain Developmental Disorders Associated with Nance-Horan Syndrome

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