1. bookVolume 30 (2022): Edizione 3 (July 2022)
Dettagli della rivista
License
Formato
Rivista
eISSN
2284-5623
Prima pubblicazione
08 Aug 2013
Frequenza di pubblicazione
4 volte all'anno
Lingue
Inglese
access type Accesso libero

Novel DCX pathogenic variant in a girl with subcortical band heterotopia

Pubblicato online: 18 Jul 2022
Volume & Edizione: Volume 30 (2022) - Edizione 3 (July 2022)
Pagine: 345 - 352
Ricevuto: 10 Dec 2021
Accettato: 22 Jun 2022
Dettagli della rivista
License
Formato
Rivista
eISSN
2284-5623
Prima pubblicazione
08 Aug 2013
Frequenza di pubblicazione
4 volte all'anno
Lingue
Inglese
Abstract

Subcortical band heterotopia (SBH), is a brain malformation defined by symmetrical and bilateral heterotopic gray matter bands localized deep within the white matter, between the cortex and lateral ventricles. SBH is the result of abnormal neuronal migration, with improper positioning of the cortical neurons. DCX gene (doublecortin), a microtubule-associated protein with essential roles in neuronal migration and differentiation during brain development, is one of the main contributors to the X-linked Lissencephaly spectrum pathogenesis (OMIM #300067). DCX variants are responsible for SBH in females and isolated lissencephaly in males. Herein, we present a 7-year-old girl with a de novo frameshift variant in DCX gene, unreported by date. The patient has focal complex seizures with onset at 23 months of age, fully controlled with medication, mild tremor and coordination impairment of fine movements and some learning difficulties, otherwise with normal development. The brain magnetic resonance imaging revealed the presence of thick SBH. Direct sequencing of DCX gene revealed a pathogenic heterozygous cytosine duplication in exon 3; this frameshift variant leads to a premature stop codon in position 164 (p.Gln160Profs*5). The variant type and its predicted consequence at protein level correlates with the severity of radiological findings. The clinical presentation of our patient is, however, milder than expected. Our research expands the mutational spectrum of DCX gene in SBH females and provides a detailed clinical and imagistic description of the patient. This paper highlights the utility of single gene sequencing as a first-tier diagnostic test of patients with gene-specific phenotypic features.

Keywords

1. Barkovich AJ, Jackson DJ, Boyer RS. Band heterotopias: a newly recognized neuronal migration anomaly. Radiology. 1989 May;171(2):455-8. DOI: 10.1148/radiology.171.2.2468173 Apri DOISearch in Google Scholar

2. Dobyns WB, Andermann E, Andermann F, Czapansky-Beilman D, Dubeau F, Dulac O, et al. X-linked malformations of neuronal migration. Neurology. 1996 Aug;47(2):331-9. DOI: 10.1212/WNL.47.2.331 Apri DOISearch in Google Scholar

3. Bahi-Buisson N, Souville I, Fourniol FJ, Toussaint A, Moores CA, Houdusse A, et al. New insights into genotype-phenotype correlations for the doublecortin-related lissencephaly spectrum. Brain. 2013 Jan;136(Pt 1):223-44. DOI: 10.1093/brain/aws323 Apri DOISearch in Google Scholar

4. Pilz DT, Matsumoto N, Minnerath S, Mills P, Glee-son JG, Allen KM, et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet. 1998 Dec;7(13):2029-37. DOI: 10.1093/hmg/7.13.2029 Apri DOISearch in Google Scholar

5. Gleeson JG, Luo RF, Grant PE, Guerrini R, Huttenlocher PR, Berg MJ, et al. Genetic and neuroradiological heterogeneity of double cortex syndrome. Ann Neurol. 2000 Feb;47(2):265-9. DOI: 10.1002/1531-8249(200002)47:2<265::AIDANA22>3.0.CO;2-N Apri DOISearch in Google Scholar

6. Reiner O. LIS1 and DCX: Implications for Brain Development and Human Disease in Relation to Microtubules. Scientifica. 2013 Mar;2013:1-17. DOI: 10.1155/2013/393975 Apri DOISearch in Google Scholar

7. Matsumoto N, Leventer RJ, Kuc JA, Mewborn SK, Dudlicek LL, Ramocki MB, et al. Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia. Eur J Hum Genet. 2001 Jan;9(1):5-12. DOI: 10.1038/sj.ejhg.5200548 Apri DOISearch in Google Scholar

8. Dobyns WB. The clinical patterns and molecular genetics of lissencephaly and subcortical band heterotopia. Epilepsia. 2010 Feb;51(Suppl. 1):5-9. DOI: 10.1111/j.1528-1167.2009.02433.x Apri DOISearch in Google Scholar

9. Bakircioglu M, Carvalho OP, Khurshid M, Cox JJ, Tuysuz B, Barak T, et al. The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. Am J Hum Genet. 2011 May; 88(5):523-35. DOI: 10.1016/j. ajhg.2011.03.019 Apri DOISearch in Google Scholar

10. Watrin F, Manent JB, Cardoso C, Represa A. Causes and Consequences of Gray Matter Heterotopia. CNS Neurosci Ther. 2015 Feb;21(2):112-22. DOI: 10.1111/cns.12322 Apri DOISearch in Google Scholar

11. Tsai MH, Muir AM, Wang WJ, Kang YN, Chao NH, Wu MF, et al. Pathogenic variants in CEP85L cause sporadic and familial posterior predominant lissencephaly. Neuron. 2020 Apr;106(2):237-245.e8. DOI: 10.1016/j.neuron.2020.01.027 Apri DOISearch in Google Scholar

12. Moslehi M, Ng DCH, Bogoyevitch MA. Dynamic microtubule association of Doublecortin X (DCX) is regulated by its C-terminus. Sci Rep. 2017 Jul;7(1):5245. DOI: 10.1038/s41598-017-05340-x Apri DOISearch in Google Scholar

13. Tint I, Jean D, Baas PW, Black MM. Doublecortin associates with microtubules preferentially in regions of the axon displaying actin-rich protrusive structures. J Neurosci. 2009 Sep;29 (35):10995-1010. DOI: 10.1523/JNEUROSCI.3399-09.2009 Apri DOISearch in Google Scholar

14. Moslehi M, Ng DCH, Bogoyevitch MA. Doublecortin X (DCX) serine 28 phosphorylation is a regulatory switch, modulating association of DCX with microtubules and actin filaments. Biochim Biophys Acta Mol Cell Res. 2019 Apr;1866(4):638-49. DOI: 10.1016/j. bbamcr.2019.01.003 Apri DOISearch in Google Scholar

15. Burger D, Stihle M, Sharma A, Di Lello P, Benz J, D’Arcy B, et al. Crystal Structures of the Human Doublecortin C- and N-terminal Domains in Complex with Specific Antibodies. J Biol Chem. 2016 Jul;291(31):16292-306. DOI: 10.1074/jbc.M116.726547 Apri DOISearch in Google Scholar

16. Kim MH, Cierpicki T, Derewenda U, Krowarsch D, Feng Y, Devedjiev Y, et al. The DCX-domain tandems of doublecortin and doublecortin-like kinase. Nat Struct Biol. 2003 May;10(5):324-33. DOI: 10.1038/nsb918 Apri DOISearch in Google Scholar

17. Manka SW, Moores CA. Pseudo-repeats in doublecortin make distinct mechanistic contributions to microtubule regulation. EMBO Rep. 2020 Dec;21(12):e51534. DOI: 10.15252/embr.202051534 Apri DOISearch in Google Scholar

18. Tanaka T, Serneo FF, Tseng HC, Kulkarni AB, Tsai LH, Gleeson JG. Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration. Neuron. 2004 Jan;41(2):215-27. DOI: 10.1016/S0896-6273(03)00852-3 Apri DOISearch in Google Scholar

19. Haverfield E, Whited A, Petras K, Dobyns W, Das S. Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia. Eur J Hum Genet. 2009 Jul;17(7):911-8. DOI: 10.1038/ejhg.2008.213298649819050731 Apri DOISearch in Google Scholar

20. Jamuar SS, Walsh CA. Genomic variants and variations in malformations of cortical development. Pediatr Clin North Am. 2015 Apr;62(3):571-585. DOI: 10.1016/j.pcl.2015.03.002444945426022163 Apri DOISearch in Google Scholar

Articoli consigliati da Trend MD

Pianifica la tua conferenza remota con Sciendo