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Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Publication ,  Journal Article
den Hoed, J; de Boer, E; Voisin, N; Dingemans, AJM; Guex, N; Wiel, L; Nellaker, C; Amudhavalli, SM; Banka, S; Bena, FS; Ben-Zeev, B; Brunet, T ...
Published in: Am J Hum Genet
February 4, 2021

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

February 4, 2021

Volume

108

Issue

2

Start / End Page

346 / 356

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Protein Domains
  • Protein Binding
  • Neurodevelopmental Disorders
  • Mutation, Missense
  • Mutation
  • Models, Molecular
  • Matrix Attachment Region Binding Proteins
  • Male
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
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den Hoed, J., de Boer, E., Voisin, N., Dingemans, A. J. M., Guex, N., Wiel, L., … Vissers, L. E. L. M. (2021). Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction. Am J Hum Genet, 108(2), 346–356. https://doi.org/10.1016/j.ajhg.2021.01.007
Hoed, Joery den, Elke de Boer, Norine Voisin, Alexander J. M. Dingemans, Nicolas Guex, Laurens Wiel, Christoffer Nellaker, et al. “Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.Am J Hum Genet 108, no. 2 (February 4, 2021): 346–56. https://doi.org/10.1016/j.ajhg.2021.01.007.
den Hoed J, de Boer E, Voisin N, Dingemans AJM, Guex N, Wiel L, et al. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction. Am J Hum Genet. 2021 Feb 4;108(2):346–56.
den Hoed, Joery, et al. “Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.Am J Hum Genet, vol. 108, no. 2, Feb. 2021, pp. 346–56. Pubmed, doi:10.1016/j.ajhg.2021.01.007.
den Hoed J, de Boer E, Voisin N, Dingemans AJM, Guex N, Wiel L, Nellaker C, Amudhavalli SM, Banka S, Bena FS, Ben-Zeev B, Bonagura VR, Bruel A-L, Brunet T, Brunner HG, Chew HB, Chrast J, Cimbalistienė L, Coon H, DDD Study, Délot EC, Démurger F, Denommé-Pichon A-S, Depienne C, Donnai D, Dyment DA, Elpeleg O, Faivre L, Gilissen C, Granger L, Haber B, Hachiya Y, Abedi YH, Hanebeck J, Hehir-Kwa JY, Horist B, Itai T, Jackson A, Jewell R, Jones KL, Joss S, Kashii H, Kato M, Kattentidt-Mouravieva AA, Kok F, Kotzaeridou U, Krishnamurthy V, Kučinskas V, Kuechler A, Lavillaureix A, Liu P, Manwaring L, Matsumoto N, Mazel B, McWalter K, Meiner V, Mikati MA, Miyatake S, Mizuguchi T, Moey LH, Mohammed S, Mor-Shaked H, Mountford H, Newbury-Ecob R, Odent S, Orec L, Osmond M, Palculict TB, Parker M, Petersen AK, Pfundt R, Preikšaitienė E, Radtke K, Ranza E, Rosenfeld JA, Santiago-Sim T, Schwager C, Sinnema M, Snijders Blok L, Spillmann RC, Stegmann APA, Thiffault I, Tran L, Vaknin-Dembinsky A, Vedovato-Dos-Santos JH, Schrier Vergano SA, Vilain E, Vitobello A, Wagner M, Waheeb A, Willing M, Zuccarelli B, Kini U, Newbury DF, Kleefstra T, Reymond A, Fisher SE, Vissers LELM. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction. Am J Hum Genet. 2021 Feb 4;108(2):346–356.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

February 4, 2021

Volume

108

Issue

2

Start / End Page

346 / 356

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Protein Domains
  • Protein Binding
  • Neurodevelopmental Disorders
  • Mutation, Missense
  • Mutation
  • Models, Molecular
  • Matrix Attachment Region Binding Proteins
  • Male
  • Humans