Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation
Date
2005
Authors
Walenkamp, M.
Karperien, M.
Pereira, A.
Hilhorst-Hofstee, Y.
van Doorn, J.
Chen, J.
Mohan, S.
Denley, A.
Forbes, B.
van Duyvenvoorde, H.
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Journal article
Citation
Journal of Clinical Endocrinology and Metabolism (JCEM), 2005; 90(5):2855-2864
Statement of Responsibility
M. J. E. Walenkamp, M. Karperien, A. M. Pereira, Y. Hilhorst-Hofstee, J. van Doorn, J. W. Chen, S. Mohan, A. Denley, B. Forbes, H. A. van Duyvenvoorde, S. W. van Thiel, C. A. Sluimers, J. J. Bax, J. A. P. M. de Laat, M. B Breuning, J. A. Romijn, and J. M. Wit
Conference Name
Abstract
IGF-I is a key factor in intrauterine development and postnatal growth and metabolism. The secretion of IGF-I in utero is not dependent on GH, whereas in childhood and adult life, IGF-I secretion seems to be mainly controlled by GH, as revealed from studies on patients with GHRH receptor and GH receptor mutations. In a 55-yr-old male, the first child of consanguineous parents, presenting with severe intrauterine and postnatal growth retardation, microcephaly, and sensorineural deafness, we found a homozygous G to A nucleotide substitution in the IGF-I gene changing valine 44 into methione. The inactivating nature of the mutation was proven by functional analysis demonstrating a 90-fold reduced affinity of recombinantly produced for the IGF-I receptor. Additional investigations revealed osteoporosis, a partial gonadal dysfunction, and a relatively well-preserved cardiac function. Nine of the 24 relatives studied carried the mutation. They had a significantly lower birth weight, final height, and head circumference than noncarriers. In conclusion, the phenotype of our patient consists of severe intrauterine growth retardation, deafness, and mental retardation, reflecting the GH-independent secretion of IGF-I in utero. The postnatal growth pattern, similar to growth of untreated GH-deficient or GH-insensitive children, is in agreement with the hypothesis that IGF-I secretion in childhood is mainly GH dependent. Remarkably, IGF-I deficiency is relatively well tolerated during the subsequent four decades of adulthood. IGF-I haploinsufficiency results in subtle inhibition of intrauterine and postnatal growth.
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© 2005 by The Endocrine Society