Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium

Olga V Fofanova-Gambetti, Vivian Hwa, Jan M Wit, Horacio M Domene, Jesús Argente, Peter Bang, Wolfgang Högler, Susan Kirsch, Catherine Pihoker, Harvey K Chiu, Laurie Cohen, Christina Jacobsen, Hector G Jasper, Gabriele Haeusler, Angel Campos-Barros, Elena Gallego-Gómez, Ricardo Gracia-Bouthelier, Hermine A van Duyvenvoorde, Jesús Pozo, Ron G Rosenfeld

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)


CONTEXT: To date, 16 IGFALS mutations in 21 patients with acid-labile subunit (ALS) deficiency have been reported. The impact of heterozygosity for IGFALS mutations on growth is unknown.

OBJECTIVE: The study evaluates the impact of heterozygous expression of IGFALS mutations on phenotype based on data collected by the International ALS Consortium.

SUBJECTS/METHODS: Patient information was derived from the IGFALS Registry, which includes patients with IGFALS mutations and family members who were either heterozygous carriers or homozygous wild-type. Within each family, the effect of IGFALS mutations on stature was analyzed as follows: 1) effect of two mutant alleles (2ALS) vs. wild-type (WT); 2) effect of two mutant alleles vs. one mutant allele (1ALS); and 3) effect of one mutant allele vs. wild-type. The differences in height sd score (HtSDS) were then pooled and evaluated.

RESULTS: Mean HtSDS in 2ALS was -2.31 +/- 0.87 (less than -2 SDS in 62%); in 1ALS, -0.83 +/- 1.34 (less than -2 SDS in 26%); and in WT, -1.02 +/- 1.04 (less than -2 SDS in 12.5%). When analyses were performed within individual families and pooled, the difference in mean HtSDS between 2ALS and WT was -1.93 +/- 0.79; between 1ALS and WT, -0.90 +/- 1.53; and between 2ALS and 1ALS, -1.48 +/- 0.83.

CONCLUSIONS: Heterozygosity for IGFALS mutations results in approximately 1.0 SD height loss in comparison with wild type, whereas homozygosity or compound heterozygosity gives a further loss of 1.0 to 1.5 SD, suggestive of a gene-dose effect. Further studies involving a larger cohort are needed to evaluate the impact of heterozygous IGFALS mutations not only on auxology, but also on other aspects of the GH/IGF system.

Original languageEnglish
Pages (from-to)4184-91
Number of pages8
JournalThe Journal of clinical endocrinology and metabolism
Issue number9
Publication statusPublished - Sept 2010


  • Adolescent
  • Adult
  • Body Height
  • Carrier Proteins
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Consensus Development Conferences as Topic
  • Family
  • Female
  • Glycoproteins
  • Growth Disorders
  • Heterozygote
  • Humans
  • International Cooperation
  • Loss of Heterozygosity
  • Male
  • Models, Biological
  • Mutation
  • Young Adult
  • Journal Article
  • Research Support, Non-U.S. Gov't


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