TY - JOUR
T1 - Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature
T2 - Results from the International Acid-Labile Subunit Consortium
AU - Fofanova-Gambetti, Olga V.
AU - Hwa, Vivian
AU - Wit, Jan M.
AU - Domene, Horacio M.
AU - Argente, Jesús
AU - Bang, Peter
AU - Högler, Wolfgang
AU - Kirsch, Susan
AU - Pihoker, Catherine
AU - Chiu, Harvey K.
AU - Cohen, Laurie
AU - Jacobsen, Christina
AU - Jasper, Hector G.
AU - Haeusler, Gabriele
AU - Campos-Barros, Angel
AU - Gallego-Gómez, Elena
AU - Gracia-Bouthelier, Ricardo
AU - Van Duyvenvoorde, Hermine A.
AU - Pozo, Jesús
AU - Rosenfeld, Ron G.
N1 - Funding Information:
A.C.-B., E.G.-G., and R.G.-B. were supported by Grant PI 09/01266 from the Fondo de Investigación Sanitaria, ISCIII, Madrid, Spain.
PY - 2010/9
Y1 - 2010/9
N2 - 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.
AB - 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.
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U2 - 10.1210/jc.2010-0489
DO - 10.1210/jc.2010-0489
M3 - Article
C2 - 20591980
AN - SCOPUS:77956571221
SN - 0021-972X
VL - 95
SP - 4184
EP - 4191
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 9
ER -