RGD Reference Report - A novel mutation in IGFALS, c.380T>C (p.L127P), associated with short stature, delayed puberty, osteopenia and hyperinsulinaemia in two siblings: insights into the roles of insulin growth factor-1 (IGF1). - Rat Genome Database

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A novel mutation in IGFALS, c.380T>C (p.L127P), associated with short stature, delayed puberty, osteopenia and hyperinsulinaemia in two siblings: insights into the roles of insulin growth factor-1 (IGF1).

Authors: Hess, Ora  Khayat, Morad  Hwa, Vivian  Heath, Karen E  Teitler, Amnon  Hritan, Yifat  Allon-Shalev, Stavit  Tenenbaum-Rakover, Yardena 
Citation: Hess O, etal., Clin Endocrinol (Oxf). 2013 Dec;79(6):838-44. doi: 10.1111/cen.12200. Epub 2013 Apr 13.
RGD ID: 12910853
Pubmed: (View Article at PubMed) PMID:23488611
DOI: Full-text: DOI:10.1111/cen.12200


BACKGROUND: The acid-labile subunit (ALS) protein is crucial for maintaining the circulating IGF/IGFBP system. Inactivating mutations of IGFALS result in IGF1 deficiency associated with growth retardation. Although the first IGFALS mutation in humans was described in 2004, only 16 mutations have been reported since. Moreover, the phenotype of affected patients as a consequence of ALS deficiency is still highly variable. We assessed whether children with idiopathic short stature (ISS) harbour mutations in IGFALS and characterized affected patients' phenotype.
DESIGN: Sixty-five children with ISS were enrolled in the study. Serum ALS levels were measured by ELISA, and IGFALS was sequenced.
RESULTS: A novel homozygous mutation in IGFALS, c.380T>C (p.L127P), was identified in two siblings of a consanguineous family. The proband, a 17·75-year-old male, was -1·9 SDS in height and -4·5 SDS in weight. Exaggerated stimulated GH (38 ng/ml) and extremely low IGF1 and IGFBP3 (<25 and <500 ng/ml, respectively) indicated GH insensitivity. Both affected siblings had low or no ALS (43 and 0 mU/ml, respectively). They were also mildly small for gestational age, severely underweight and showed osteopenia, insulin insensitivity and delayed and slow puberty progression.
CONCLUSIONS: Acid-labile subunit deficiency due to IGFALS mutations is a rare cause of growth retardation in children. The unique combination of features presented by the two affected siblings emphasizes the important role of IGF1 in bone formation, insulin regulation and the pubertal process, in addition to its crucial effect on growth. Long-term follow-up is indicated since the clinical outcome with respect to osteoporosis, diabetes mellitus and fertility has not been recognized.

Annotation

Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Igfals  (insulin-like growth factor binding protein, acid labile subunit)

Genes (Mus musculus)
Igfals  (insulin-like growth factor binding protein, acid labile subunit)

Genes (Homo sapiens)
IGFALS  (insulin like growth factor binding protein acid labile subunit)


Additional Information