Functionally significant insulin-like growth factor I receptor mutations in centenarians
- Yousin Suh*,
- Gil Atzmon†,
- Mi-Ook Cho*,
- David Hwang‡,
- Bingrong Liu‡,
- Daniel J. Leahy§,
- Nir Barzilai†,¶, and
- Pinchas Cohen‡
- *Departments of Medicine and Molecular Genetics, and
- †Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461;
- ‡Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and
- §Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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Edited by Cynthia J. Kenyon, University of California, San Francisco, CA, and approved January 18, 2008 (received for review June 11, 2007)
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Fig. 1.Phenotypes and chemotypes of the IGF system in the centenarian cohort. (A) Female offspring of centenarians (n = 105) have higher serum IGFI levels compared with age-matched female controls without a family history of unusual longevity (n = 67). IGFI levels in male offspring (n = 92) and male controls (n = 42) were identical. IGFI levels in serum were measured by ELISA (*, P < 0.01). Results are reported as mean ± SD. (B) Female offspring are shorter than controls as measured by maximal reported height (**, P < 0.001). Results are reported as mean ± SD. (C) Immortalized lymphocytes from the female centenarians carrying mutations (Carrier) in IGF1R (Ala-37–Thr, Arg-407–His, and Thr-470–Thr) show significant reductions in IGFIR levels compared with immortalized lymphocytes from female centenarians with no mutations (Noncarrier, n = 10) as measured by ELISA (⋀, P < 0.03). (D) IGF signaling is defective in the IGF1R mutation carriers (Carrier) of female centenarians as compared with female centenarians with no mutations (Noncarrier, n = 10) as measured by immunoblot analysis of the ratio of phosphorylated to total AKT in response to IGFI treatment in immortalized lymphocytes. (E) A representative immunoblot for total and phosphorylated AKT in immortalized lymphocytes from a centenarian carrying the Arg-407–His mutation and a control centenarian without the mutation.
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Fig. 2.2D gene scanning of human IGF1 and IGF1R genes. The entire coding regions and exon–intron junctions of the IGF1 and IGF1R genes were amplified by two-step PCR. Thirty short PCR fragments were distributed in 2D gels according to their size and melting temperature. (A) A 2D gene scanning pattern from a centenarian subject with the fragment identification number and a hetero-duplex band in exon 8.1 and exon 6 of the IGF1Rgene is shown. (B) The novel genetic variation in exon 6 was identified as 1355G>A (Arg-407–His) by nucleotide sequencing.
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Fig. 3.The position of mutated amino acids in the IGFIR. The locations of the mutated amino acids are indicated in the crystallographic structure encompassing the first three domains of the IGFIR (L1-CR-L2 fragment) (24). Color-coded residues are those when mutated reduce the binding affinity of IGFI for IGFIR by 2- to 10-fold (pale pink) or >20-fold (red) (23) or a compound heterozygote missense mutations (hot pink) from a patient with intrauterine and postnatal growth retardation (22). Arrows indicate the locations of the mutated amino acids identified in centenarians.
Footnotes
- ¶To whom correspondence should be addressed. E-mail: barzilai{at}aecom.yu.edu
- © 2008 by The National Academy of Sciences of the USA
