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This Article Full Text Full Text (PDF) All Versions of this Article: EJE-08-0081v1 159/2/113    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by van Duyvenvoorde, H A Articles by Hermus, A R M M PubMed PubMed Citation Articles by van Duyvenvoorde, H A Articles by Hermus, A R M M

Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit

¹ Departments of Paediatrics² , Endocrinology and Metabolic Diseases³ Center for Human and Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands⁴ Department of Endocrinology, University Medical Center Nijmegen, Radboud University, Nijmegen, The Netherlands⁵ Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Utrecht, The Netherlands⁶ Department of Paediatrics, University Medical Center Maastricht, Maastricht, The Netherlands⁷ Department of Paediatrics, University Medical Center Nijmegen, Radboud University, Nijmegen, The Netherlands⁸ Department of Tissue Regeneration, University of Twente, Enschede, The Netherlands

(Correspondence should be addressed to H A van Duyvenvoorde who is now at Department of Human and Clinical Genetics, C4-R, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; Email: h.a.van_duyvenvoorde{at}lumc.nl)

Context: Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown.

Objective: To investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers.

Subjects: Three short Kurdish brothers and their relatives.

Results: The index cases presented with short stature, microcephaly, and low circulating IGF-I and IGF-binding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives.

Conclusions: The clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.