IGFALS – Short Stature Due to Primary Acid-Labile Subunit Deficiency

Autosomal recessive pathogenic variants in IGFALS underlie short stature due to primary acid-labile subunit deficiency, a disorder marked by impaired stabilization of circulating IGF-I and IGFBP-3. Patients present postnatal growth delay (HP:0001510) associated with low serum IGF-I, IGFBP-3, and absent or reduced acid-labile subunit (ALS) levels. Bi‐allelic inactivating mutations are required for full‐blown disease, whereas heterozygous carriers may show milder phenotypes.

Genetic evidence includes four unrelated index cases and four affected relatives with bi‐allelic IGFALS variants exhibiting consistent ACLSD features ([PMID:28445628]). A single patient homozygous for D440N (c.1318G>A (p.Asp440Asn)) also manifested mild growth retardation and deficient ternary complex formation ([PMID:21177759]). In total, at least five probands across five distinct families have been reported, with segregation in four additional relatives.

Case series identified multiple variant classes: frameshift mutations p.Glu35Glyfs*17 and p.Glu35Lysfs*87, and missense substitutions p.Ser490Trp, p.Cys540Arg, p.Asn276Ser, p.Leu409Phe, and p.Arg548Trp shown to abolish or severely reduce protein synthesis or secretion ([PMID:27018247], [PMID:28445628]). Partial secretion defects were noted for p.Ala330Asp and p.Ala475Val, which nonetheless retained ternary complex formation capacity ([PMID:27018247]).

Functional assays across studies corroborate a loss‐of‐function mechanism. In vitro expression in CHO cells and Western immunoblotting demonstrated absent or markedly reduced ALS protein for seven variants, while gel‐filtration chromatography confirmed defective IGF-I–IGFBP-3 complex formation for D440N and related glycosylation‐altering mutants ([PMID:21177759], [PMID:27018247]). These concordant data establish the mechanistic basis for impaired IGF bioavailability.

Variants in IGFALS have also been identified in heterozygous state in idiopathic short stature cohorts without full ALS deficiency, suggesting limited penetrance or modifier effects in single‐allele carriers ([PMID:28768959]). No studies to date refute the association of bi‐allelic IGFALS loss with ACLSD.

Overall, the gene–disease association is classified as Moderate based on five probands in five families, segregation in four relatives, and robust in vitro functional concordance. Clinical IGFALS testing should be considered in suspected ACLSD to guide growth hormone therapy and genetic counseling.

References

• Clinical Endocrinology • 2017 • Characterization of four Latin American families confirms previous findings and reveals novel features of acid-labile subunit deficiency. PMID:28445628
• Molecular Endocrinology (Baltimore, Md.) • 2011 • D440N mutation in the acid-labile subunit of insulin-like growth factor complexes inhibits secretion and complex formation. PMID:21177759
• Molecular and Cellular Endocrinology • 2016 • Assessment of pathogenicity of natural IGFALS gene variants by in silico bioinformatics tools and in vitro functional studies PMID:27018247
• Endocrine Journal • 2017 • Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature. PMID:28768959

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