IGF-I Allele in Small Size Dogs

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Intrigued by the great diversity in size among the dog family (Canidae), these investigators first identified by genome-wide scan a skeletal size-related quantitative trait locus (QTL) on chromosome 15 within a single breed - the Portuguese water dog (PWD), a breed with great inter-individual variation in size. They next examined the relationship of single-nucleotide polymorphisms (SNPs) within this QTL to skeletal size in large and small Portuguese water dogs. They found one such SNP in this QTL to be associated with size that was near the gene encoding insulin-like growth factor-I (IGF1). Designating the haplotypes I and B, the investigators found that Portuguese water dogs homozygous for haplotype I were larger in size and had higher serum IGF-I concentrations than did dogs that were homozygous for haplotype B; they calculated that 15% of the variability of skeletal size within this breed could be accounted for by this IGF1 haplotype (Figure 1). Performing the same SNP analyses in more size-homogeneous small (n=23, <9 kg) and giant (n=20, >30 kg) canid breeds, the authors found skeletal size to be related to an IGF1 haplotype characterized by 20 SNPs that was shared by all small breed dogs (and one in particular designated SNP 5 A) (Figure 2). Sequencing of IGF1 revealed a SNP in exon 3 and several SNPs in flanking genomic sequences (promoter region) and introns that were unique to small breeds but no specific variant related to size was definitely identified. The authors concluded that “a narrow ... genomic region holds the variant ... (in IGF1) ... responsible for ... size in a disparate set of small ... (and giant) ... dog breeds ... ”

Sutter NB, Bustamante CD, Chase K, et al. A single IGF1 allele is a major determinant of small size in dogs. Science. 2007;316:112-15.

Figure 1. Serum levels of IGF1 protein (ng/ml) as a function of haplotype. Serum levels of IGF1 protein were assayed in 31 PWDs carrying haplotypes B and I. Box plots show the median (center line in box), first and third quartile (box ends), and maximum and minimum values (whiskers) obtained for each category: homozygous B/B (n = 15), heterozygous B/I (n =7), and homozygous I/I (n =9). Reprinted with permission from Sutter NB, et al. Science. 2007;316:112-15. Copyright © AAAS 2007. All rights reserved.

Figure 2. Association of body size and frequency of the SNP 5 A allele. Binomial regression of allele frequency on square root of mean breed mass. Dashed lines indicate the 95% confidence interval on the predicted equation line as estimated from nonparametric bootstrap resampling. Between 5 and 109 (median = 22) dogs were genotyped for each of 143 breeds. The PWD is highlighted in red along with three giant breeds that have larger breed average masses than is predicted by their SNP 5 allele frequency. Reprinted with permission from Sutter NB, et al. Science. 2007;316:112-5. Copyright © AAAS 2007. All rights reserved.

Editor’s Comment

Although previous studies have identified a relationship between serum levels of IGF-I in various dog breeds and have been related to growth in humans, the fact that it is tissue and not serum IGF-I values that determine growth must be remembered.1 The findings in this report should in no way be construed or utilized to support the use of recombinant human (rh) IGF-I in the treatment of children with idiopathic short stature, a contentious practice.2 The use of rhIGF-I is of limited value in patients with severe IGF-I deficiency due to growth hormone (GH) resistance due to inactivating mutations of the genes encoding the GH receptor or STAT5 or due to development of neutralizing antibodies to rhGH; it is not indicated nor particularly efficacious in other short stature children while exposing them to significant risks.

Allen W. Root, MD

References - (linked to )

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