LHX4 R84C - GET-Evidence

Curation:
Currentness:

LHX4 R84C

(LHX4 Arg84Cys)


You are viewing the latest version of this page, saved on November 28, 2013 at 10:00am by Madeleine Ball.

Short summary

A rare variant reported to cause growth hormone deficiency in a dominant manner. No statistical was established — only one case report in a screen of 245 families, and no controls reported.

Variant evidence
Computational 2

Polyphen 2 predicts damaging effect, and other variants in this gene are associated with growth hormone deficiency

Functional 1

Reduced protein levels observed in vitro, but normal binding

See Pfaeffle RW et al. 2008 (18073311).

Case/Control

No statistical significance

See Pfaeffle RW et al. 2008 (18073311).

Familial

No familial segregation reported

See Pfaeffle RW et al. 2008 (18073311).

 
Clinical importance
Severity 4

can have a severe effect on stature

Treatability 4

treatable with hormone supplementation

Penetrance 5

Reported as a “mendelian” high penetrance mutation

 

Impact

High clinical importance, Uncertain pathogenic

(The "high clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

dominant

Summary of published research, and additional commentary

 

Allele frequency

  • None available.

Publications
 

Edited in this revision:

Pfaeffle RW, Hunter CS, Savage JJ, Duran-Prado M, Mullen RD, Neeb ZP, Eiholzer U, Hesse V, Haddad NG, Stobbe HM, Blum WF, Weigel JF, Rhodes SJ. Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. J Clin Endocrinol Metab. 2008 Mar;93(3):1062-71. Epub 2007 Dec 11. PubMed PMID: 18073311; PubMed Central PMCID: PMC2266965.

This study screened 253 patients from 245 families with growth hormone deficiency for variants in LHX4. Five patients from three families were identified with LHX4 variants which the authors describe as causal, including one individual with Macedonian ancestry carrying this variant. No controls are reported.

In vitro testing found this protein to have normal interactions with other proteins, but reduced protein levels, leading the authors to hypothesize that the variant reduces stability.

Genomes
 

Other external references
 

    PolyPhen-2
  • Score: 1.0 (probably damaging)
    Web search results (10 hits -- see all)
  • Three Novel Missense Mutations within the LHX4 Gene Are ...
    Context: The LHX4 LIM-homeodomain transcription factor has essential ... Wild-type LHX4 activates the GSU reporter (23- fold), whereas R84C has reduced ...
    jcem.endojournals.org/cgi/content/full/93/3/1062
  • Three Novel Missense Mutations within the LHX4 Gene Are ...
    Affinity resins containing either recombinant wild-type or R84C LHX4 proteins (as GST fusions) were incubated with radiolabeled PIT1 proteins. ...
    jcem.endojournals.org/cgi/content/full/93/3/1062/F5
  • OMIM: 602146
    Lhx3 and Lhx4 have redundant control over formation of the definitive ... to-cys substitution at codon 84, between the LIM domains of the protein (R84C) ...
    www.genome.jp/dbget-bin/www_bget?omim+602146
  • Rarity of PIT1 involvement in children from Russia with ...
    BioInfoBank Library :: Rarity of PIT1 involvement in children from Russia with combined pituitary hormone deficiency. A case of severe pituitary dwarfism associated ...
    lib.bioinfo.pl/pmid:9632165

Other in silico analyses
 

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 5

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in