Skip to main content
Journal cover image

De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.

Publication ,  Journal Article
Chong, JX; McMillin, MJ; Shively, KM; Beck, AE; Marvin, CT; Armenteros, JR; Buckingham, KJ; Nkinsi, NT; Boyle, EA; Berry, MN; Bocian, M ...
Published in: Am J Hum Genet
March 5, 2015

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

March 5, 2015

Volume

96

Issue

3

Start / End Page

462 / 473

Location

United States

Related Subject Headings

  • Sodium Channels
  • Mutation, Missense
  • Muscle Hypotonia
  • Membrane Proteins
  • Male
  • Ion Channels
  • Infant
  • Humans
  • Homozygote
  • High-Throughput Nucleotide Sequencing
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chong, J. X., McMillin, M. J., Shively, K. M., Beck, A. E., Marvin, C. T., Armenteros, J. R., … Bamshad, M. J. (2015). De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet, 96(3), 462–473. https://doi.org/10.1016/j.ajhg.2015.01.003
Chong, Jessica X., Margaret J. McMillin, Kathryn M. Shively, Anita E. Beck, Colby T. Marvin, Jose R. Armenteros, Kati J. Buckingham, et al. “De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.Am J Hum Genet 96, no. 3 (March 5, 2015): 462–73. https://doi.org/10.1016/j.ajhg.2015.01.003.
Chong JX, McMillin MJ, Shively KM, Beck AE, Marvin CT, Armenteros JR, et al. De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet. 2015 Mar 5;96(3):462–73.
Chong, Jessica X., et al. “De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.Am J Hum Genet, vol. 96, no. 3, Mar. 2015, pp. 462–73. Pubmed, doi:10.1016/j.ajhg.2015.01.003.
Chong JX, McMillin MJ, Shively KM, Beck AE, Marvin CT, Armenteros JR, Buckingham KJ, Nkinsi NT, Boyle EA, Berry MN, Bocian M, Foulds N, Uzielli MLG, Haldeman-Englert C, Hennekam RCM, Kaplan P, Kline AD, Mercer CL, Nowaczyk MJM, Klein Wassink-Ruiter JS, McPherson EW, Moreno RA, Scheuerle AE, Shashi V, Stevens CA, Carey JC, Monteil A, Lory P, Tabor HK, Smith JD, Shendure J, Nickerson DA, University of Washington Center for Mendelian Genomics, Bamshad MJ. De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet. 2015 Mar 5;96(3):462–473.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

March 5, 2015

Volume

96

Issue

3

Start / End Page

462 / 473

Location

United States

Related Subject Headings

  • Sodium Channels
  • Mutation, Missense
  • Muscle Hypotonia
  • Membrane Proteins
  • Male
  • Ion Channels
  • Infant
  • Humans
  • Homozygote
  • High-Throughput Nucleotide Sequencing