Wit Jan M, Walenkamp Marie J
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
World Rev Nutr Diet. 2013;106:60-5. doi: 10.1159/000342546. Epub 2013 Feb 11.
Information about the role of insulin-like growth factors (IGFs) is mainly derived from knockout (KO) and transgenic mice, human mutations in IGF1, IGF1R and IGFALS, and association studies with IGF1 SNPs. Igf1 KO mice show severely impaired pre- and postnatal growth and brain development and sensorineural hearing loss. Both local and endocrine IGF-1 are needed for normal growth. Igfals KO mice show a modest postnatal growth attenuation. Homozygous igf1r KO mice are severely growth impaired, while heterozygous mutations only show mild growth retardation. Two patients with a complete absence of biologically active IGF-1 showed severe pre- and postnatal growth, extreme microcephaly, sensorineural deafness and failure to thrive. A patient with a mutation that led to a partially functional protein had a less severe growth phenotype and no deafness, similarly to two siblings with a heterozygous IGF1 mutation. Heterozygosity for a dysfunctional IGF1 mutation leads to a mild effect on birth weight, adult height and head circumference. Patients with heterozygous mutations or deletions of IGF1R have a moderate pre- and postnatal growth failure, microcephaly and a history of feeding problems. Children with homozygous mutations of IGFALS have a low or normal birth weight, a mild growth failure, a head circumference in the lower normal range, and no failure to thrive. Association studies of IGF1 polymorphisms in large populations have shown variable results with respect to height, but a more consistent association with head circumference. In conclusion, a normal IGF-I bioactivity (normal local and endocrine IGF-1 availability, normal IGF1R function, normal signaling) is needed for a normal pre- and postnatal longitudinal and cranial growth. IGF-1 dysfunction causes severe growth failure, while heterozygous defects of IGF1R and homozygous defects of IGFALS are associated with a milder phenotype. Feeding disturbances in infants with IGF1 and IGF1R mutations suggest a role of IGF-1 signaling in regulatory brain centers.
关于胰岛素样生长因子（IGFs）作用的信息主要来自基因敲除（KO）小鼠和转基因小鼠、IGF1、IGF1R和IGFALS的人类突变，以及与IGF1单核苷酸多态性（SNP）的关联研究。Igf1基因敲除小鼠在出生前和出生后的生长以及大脑发育和感觉神经性听力丧失方面均表现出严重受损。正常生长需要局部和内分泌IGF-1。Igfals基因敲除小鼠出生后生长有适度减缓。纯合子igf1r基因敲除小鼠生长严重受损，而杂合子突变仅表现出轻度生长迟缓。两名完全缺乏生物活性IGF-1的患者在出生前和出生后均出现严重生长、极度小头畸形、感觉神经性耳聋和发育不良。一名发生导致部分功能性蛋白突变的患者生长表型较轻且无耳聋，这与两名携带杂合子IGF1突变的兄弟姐妹情况相似。功能失调的IGF1突变杂合性对出生体重、成人身高和头围有轻微影响。IGF1R杂合子突变或缺失的患者在出生前和出生后有中度生长发育不良、小头畸形和喂养问题史。IGFALS纯合子突变的儿童出生体重低或正常，有轻度生长发育不良，头围在正常范围下限，且无发育不良。在大量人群中对IGF1多态性的关联研究在身高方面显示出不同结果，但与头围的关联更为一致。总之，正常的出生前和出生后纵向及颅骨生长需要正常的IGF-I生物活性（正常的局部和内分泌IGF-1可用性、正常的IGF1R功能、正常的信号传导）。IGF-1功能障碍导致严重生长发育不良，而IGF1R杂合子缺陷和IGFALS纯合子缺陷与较轻的表型相关。IGF1和IGF1R突变婴儿的喂养障碍表明IGF-1信号在调节脑中枢中起作用。
