Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations

R. A. Kumar, S. Leach, R. Bonaguro, J. Chen, D. W. Yokom, B. S. Abrahams, L. Seaver, C. E. Schwartz, W. Dobyns, A. Brooks-Wilson, E. M. Simpson

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain-behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1-/- mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain-behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role.

Original languageEnglish (US)
Pages (from-to)503-516
Number of pages14
JournalGenes, Brain and Behavior
Volume6
Issue number6
DOIs
StatePublished - Aug 2007
Externally publishedYes

Fingerprint

Cytoplasmic and Nuclear Receptors
Mutation
Haplotypes
Brain
Transcription Factors
Oceania
Binding Sites
Untranslated Regions
Microcephaly
Middle East
Molecular Evolution
Linkage Disequilibrium
Hominidae
Computer Simulation
Haplorhini
Molecular Biology
Clone Cells

Keywords

  • 'fierce' mice
  • Cortex
  • Mental retardation
  • Microcephaly
  • Nuclear receptor
  • Tlx

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics

Cite this

Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations. / Kumar, R. A.; Leach, S.; Bonaguro, R.; Chen, J.; Yokom, D. W.; Abrahams, B. S.; Seaver, L.; Schwartz, C. E.; Dobyns, W.; Brooks-Wilson, A.; Simpson, E. M.

In: Genes, Brain and Behavior, Vol. 6, No. 6, 08.2007, p. 503-516.

Research output: Contribution to journalArticle

Kumar, RA, Leach, S, Bonaguro, R, Chen, J, Yokom, DW, Abrahams, BS, Seaver, L, Schwartz, CE, Dobyns, W, Brooks-Wilson, A & Simpson, EM 2007, 'Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations', Genes, Brain and Behavior, vol. 6, no. 6, pp. 503-516. https://doi.org/10.1111/j.1601-183X.2006.00277.x
Kumar, R. A. ; Leach, S. ; Bonaguro, R. ; Chen, J. ; Yokom, D. W. ; Abrahams, B. S. ; Seaver, L. ; Schwartz, C. E. ; Dobyns, W. ; Brooks-Wilson, A. ; Simpson, E. M. / Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations. In: Genes, Brain and Behavior. 2007 ; Vol. 6, No. 6. pp. 503-516.
@article{6b796a21fe034b73a4aa1a19ce7e384c,
title = "Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations",
abstract = "Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain-behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1-/- mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain-behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role.",
keywords = "'fierce' mice, Cortex, Mental retardation, Microcephaly, Nuclear receptor, Tlx",
author = "Kumar, {R. A.} and S. Leach and R. Bonaguro and J. Chen and Yokom, {D. W.} and Abrahams, {B. S.} and L. Seaver and Schwartz, {C. E.} and W. Dobyns and A. Brooks-Wilson and Simpson, {E. M.}",
year = "2007",
month = "8",
doi = "10.1111/j.1601-183X.2006.00277.x",
language = "English (US)",
volume = "6",
pages = "503--516",
journal = "Genes, Brain and Behavior",
issn = "1601-1848",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations

AU - Kumar, R. A.

AU - Leach, S.

AU - Bonaguro, R.

AU - Chen, J.

AU - Yokom, D. W.

AU - Abrahams, B. S.

AU - Seaver, L.

AU - Schwartz, C. E.

AU - Dobyns, W.

AU - Brooks-Wilson, A.

AU - Simpson, E. M.

PY - 2007/8

Y1 - 2007/8

N2 - Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain-behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1-/- mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain-behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role.

AB - Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain-behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1-/- mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain-behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role.

KW - 'fierce' mice

KW - Cortex

KW - Mental retardation

KW - Microcephaly

KW - Nuclear receptor

KW - Tlx

UR - http://www.scopus.com/inward/record.url?scp=34547840237&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547840237&partnerID=8YFLogxK

U2 - 10.1111/j.1601-183X.2006.00277.x

DO - 10.1111/j.1601-183X.2006.00277.x

M3 - Article

VL - 6

SP - 503

EP - 516

JO - Genes, Brain and Behavior

JF - Genes, Brain and Behavior

SN - 1601-1848

IS - 6

ER -