Schoch K, Meng L, Szelinger S, Bearden DR, Stray-Pedersen A, Busk OL, Stong N, Liston E, Cohn RD, Scaglia F, Rosenfeld JA, Tarpinian J, Skraban CM, Deardorff MA, Friedman JN, Akdemir ZC, Walley N, Mikati MA, Kranz PG, Jasien J, McConkie-Rosell A, McDonald M, Wechsler SB, Freemark M, Kansagra S, Freedman S, Bali D, Millan F, Bale S, Nelson SF, Lee H, Dorrani N; UCLA Clinical Genomics Center; Undiagnosed Diseases Network; Goldstein DB, Xiao R, Yang Y, Posey JE, Martinez-Agosto JA, Lupski JR, Wangler MF, Shashi V. A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay. Am J Hum Genet. 2017 Feb 2;100(2):343-351. doi: 10.1016/j.ajhg.2016.12.013. Epub 2017 Jan 26. PMID: 28132692; PMCID: PMC5294886.
Abstract
Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10-14). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.
Komulainen-Ebrahim J, Kangas SM, López-Martín E, Feyma T, Scaglia F, Martínez-Delgado B, Kuismin O, Suo-Palosaari M, Carr L, Hinttala R, Kurian MA, Uusimaa J. Hyperkinetic Movement Disorder Caused by the Recurrent c.892C>T NACC1 Variant. Mov Disord Clin Pract. 2024 Jun;11(6):708-715. doi: 10.1002/mdc3.14051. Epub 2024 May 2. PMID: 38698576; PMCID: PMC11145100.
Abstract
Background: Genetic syndromes of hyperkinetic movement disorders associated with epileptic encephalopathy and intellectual disability are becoming increasingly recognized. Recently, a de novo heterozygous NACC1 (nucleus accumbens-associated 1) missense variant was described in a patient cohort including one patient with a combined mitochondrial oxidative phosphorylation (OXPHOS) deficiency.
Objectives: The objective is to characterize the movement disorder in affected patients with the recurrent c.892C>T NACC1 variant and study the NACC1 protein and mitochondrial function at the cellular level.
Methods: The movement disorder was analyzed on four patients with the NACC1 c.892C>T (p.Arg298Trp) variant. Studies on NACC1 protein and mitochondrial function were performed on patient-derived fibroblasts.
Results: All patients had a generalized hyperkinetic movement disorder with chorea and dystonia, which occurred cyclically and during sleep. Complex I was found altered, whereas the other OXPHOS enzymes and the mitochondria network seemed intact in one patient.
Conclusions: The movement disorder is a prominent feature of NACC1-related disease.
Daniel JA, Elizarova S, Shaib AH, Chouaib AA, Magnussen HM, Wang J, Brose N, Rhee J, Tirard M. An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission. Front Mol Neurosci. 2023 Jul 14;16:1115880. doi: 10.3389/fnmol.2023.1115880. PMID: 37533751; PMCID: PMC10393139.
Abstract
Advances in genome sequencing technologies have favored the identification of rare de novo mutations linked to neurological disorders in humans. Recently, a de novo autosomal dominant mutation in NACC1 was identified (NM_052876.3: c.892C > T, NP_443108.1; p.Arg298Trp), associated with severe neurological symptoms including intellectual disability, microcephaly, and epilepsy. As NACC1 had never before been associated with neurological diseases, we investigated how this mutation might lead to altered brain function. We examined neurotransmission in autaptic glutamatergic mouse neurons expressing the murine homolog of the human mutant NACC1, i.e., Nacc1-R284W. We observed that expression of Nacc1-R284W impaired glutamatergic neurotransmission in a cell-autonomous manner, likely through a dominant negative mechanism. Furthermore, by screening for Nacc1 interaction targets in the brain, we identified SynGAP1, GluK2A, and several SUMO E3 ligases as novel Nacc1 interaction partners. At a biochemical level, Nacc1-R284W exhibited reduced binding to SynGAP1 and GluK2A, and also showed greatly increased SUMOylation. Ablating the SUMOylation of Nacc1-R284W partially restored its interaction with SynGAP1 but did not restore binding to GluK2A. Overall, these data indicate a role for Nacc1 in regulating glutamatergic neurotransmission, which is substantially impaired by the expression of a disease-associated Nacc1 mutant. This study provides the first functional insights into potential deficits in neuronal function in patients expressing the de novo mutant NACC1 protein.
Wu J, Gan J, Hua Y, Li Y, Qie D. Case report: A novel de novo variant of NACC1 caused epileptic encephalopathy and intellectual disability. Front Psychiatry. 2024 Oct 3;15:1446698. doi: 10.3389/fpsyt.2024.1446698. PMID: 39421062; PMCID: PMC11484253.
Abstract
Background: Genetic disorders could also contribute to intellectual disability. Using whole exome sequencing (WES), several variants have been identified as autosomal-dominant inheritance intellectual disability. Thus, the application of WES has demonstrated its critical role in distinguishing intellectual disability in children patients, which provides essential diagnosis and promotes therapeutic strategy.
Case presentation: The proband, an 18-month-old female patient, presented with a complex clinical profile characterized by profound developmental delay, epilepsy, and neurological developmental impairment. WES identified a heterozygous c.913A>G variant in exon 2 of NACC1, resulting in disease caused by a change in the amino acid sequence, affecting the protein features and resulting in splice site changes, as revealed by MutationTaster analysis. The protein structure of NAC1 was built and named AF-Q96RE7-F1, and the mutant site was beyond the BTB/POZ, NLS, and BEN domains. Subsequently, PyMOL software was used to illustrate the molecular structure between the wild type and the mutant type of NAC1. The residues around the 304 site of amino acid changed in NAC1 p.T304A with an altered hydrogen bond, indicating an unstable structure. The patient was diagnosed with intellectual disability and profound developmental delay with epilepsy harboring a novel de novo NACC1 variant. Upon hospital admission, a comprehensive treatment regimen was initiated, including antiseizure medications, nutritional supplements, and rehabilitation training. As a result, the patient's movement performance improved. However, recurrent epilepsy attacks still occurred.
Conclusion: This is the first case revealing a novel NACC1 c.903A>G variant that induced a neurological impairment in an infant. This report expanded the understanding of the non-domain-associated variant of NACC1 and developmental disorder.
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