Homozygous and Heterozygous Expression of a Novel Insulin-Like Growth Factor-I Mutation

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.

Older men with low serum IGF-1 have an increased risk of incident fractures: The MrOS Sweden study

“…(1)(2)(3)11) A role of IGF-1 in bone metabolism is supported by the fact that patients with IGF deficiency as a result of IGF1 gene deletion or inactivating mutation display osteopenia. (12)(13)(14) The association between serum IGF-1 and BMD has been evaluated in several cohorts but with conflicting results. (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) A positive association has been reported in some studies, (15,17,(20)(21)(22)(23)25,26) whereas no association has been found in other studies.…”

Insulin-like growth factor signaling regulates zebrafish embryonic growth and development by promoting cell survival and cell cycle progression

“…5 Clinical studies have shown that human patients with lossof-function mutations in either IGF-1 or the IGF1R suffer severe intrauterine growth restriction and poor postnatal growth, as well as microcephaly, deafness and mental retardation. [6][7][8][9][10] Mouse genetic studies further established the causational importance of IGF1R signaling in fetal growth and development. IGF1R null mutant mice exhibited severe growth retardation at birth (45% of wild-type littermates) and died shortly after birth from respiratory failure.…”

Intragenic deletions of the IGF1 receptor gene in five individuals with psychiatric phenotypes and developmental delay

“…These were located in exons 2, 7, 11 and 16, respectively. [1][2][3][4][5] Short stature was present in all cases, mild motor and/or speech developmental delay in 4/9 cases and mild intellectual disabilitywith a Wechsler intelligence quotient of 60 -in one case of a patient with a missense mutation in exon 11. This missense mutation was detected in a girl whose mother, a carrier of the same mutation, did not show any neuropsychiatric abnormalities and had normal intelligence.…”

“…They were associated with various constellations of clinical findings, including growth deficit, microcephaly, developmental delay, mild facial dysmorphisms and skeletal deformations in affected individuals. [1][2][3][4][5][6][7][8][9][10][11] Usually intrauterine or postnatal growth deficits were moderate to severe in these patients. Notably, cognitive dysfunction of the reported individuals was either moderate, mild or absent.…”

“…Missense and nonsense mutations in IGF1R segregated with short stature, mild dysmorphic facial features, mostly mild developmental delay and mild psychiatric features in one reported case. [1][2][3][4][5] Although the variable phenotype of previously reported patients with 15q26.3 deletions may be attributable, at least in part, to genes other than IGF1R, it is notable that the smallest IGF1R deletion reported to date segregated predominantly with short stature and no or mild neuropsychiatric disorders. 10 In that family described by Veenma et al, seven family members carried a deletion of exons 11-21 of the IGF1R gene and what at the time of publication used to be a hypothetical protein-locus (LOC145814), and is now annotated as a RefSeq gene, PGPEP1L, encoding pyroglutamyl-peptidase-I-like.…”