Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus

Susanne M. Clee, Brian S. Yandell, Kathryn M. Schueler, Mary E. Rabaglia, Oliver C. Richards, Summer M. Raines, Edward A. Kabara, Daniel M. Klass, Eric T.K. Mui, Donald S. Stapleton, Mark P. Gray-Keller, Matthew B. Young, Jonathan P. Stoehr, Hong Lan, Igor Boronenkov, Phil Raess, Matthew T. Flowers, Alan D. Attie

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.

Original languageEnglish (US)
Pages (from-to)688-693
Number of pages6
JournalNature genetics
Volume38
Issue number6
DOIs
StatePublished - Jun 1 2006
Externally publishedYes

Fingerprint

Quantitative Trait Loci
Type 2 Diabetes Mellitus
Organism Cloning
Chromosomes, Human, Pair 19
Insulin
Genes
Pericytes
Platelet-Derived Growth Factor
Amino Acid Substitution
Leptin
Microvessels
Introns
Exons
Fasting
Intercellular Signaling Peptides and Proteins
Obesity
Alleles
Phenotype

ASJC Scopus subject areas

  • Genetics

Cite this

Clee, S. M., Yandell, B. S., Schueler, K. M., Rabaglia, M. E., Richards, O. C., Raines, S. M., ... Attie, A. D. (2006). Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nature genetics, 38(6), 688-693. https://doi.org/10.1038/ng1796

Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. / Clee, Susanne M.; Yandell, Brian S.; Schueler, Kathryn M.; Rabaglia, Mary E.; Richards, Oliver C.; Raines, Summer M.; Kabara, Edward A.; Klass, Daniel M.; Mui, Eric T.K.; Stapleton, Donald S.; Gray-Keller, Mark P.; Young, Matthew B.; Stoehr, Jonathan P.; Lan, Hong; Boronenkov, Igor; Raess, Phil; Flowers, Matthew T.; Attie, Alan D.

In: Nature genetics, Vol. 38, No. 6, 01.06.2006, p. 688-693.

Research output: Contribution to journalArticle

Clee, SM, Yandell, BS, Schueler, KM, Rabaglia, ME, Richards, OC, Raines, SM, Kabara, EA, Klass, DM, Mui, ETK, Stapleton, DS, Gray-Keller, MP, Young, MB, Stoehr, JP, Lan, H, Boronenkov, I, Raess, P, Flowers, MT & Attie, AD 2006, 'Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus', Nature genetics, vol. 38, no. 6, pp. 688-693. https://doi.org/10.1038/ng1796
Clee SM, Yandell BS, Schueler KM, Rabaglia ME, Richards OC, Raines SM et al. Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nature genetics. 2006 Jun 1;38(6):688-693. https://doi.org/10.1038/ng1796
Clee, Susanne M. ; Yandell, Brian S. ; Schueler, Kathryn M. ; Rabaglia, Mary E. ; Richards, Oliver C. ; Raines, Summer M. ; Kabara, Edward A. ; Klass, Daniel M. ; Mui, Eric T.K. ; Stapleton, Donald S. ; Gray-Keller, Mark P. ; Young, Matthew B. ; Stoehr, Jonathan P. ; Lan, Hong ; Boronenkov, Igor ; Raess, Phil ; Flowers, Matthew T. ; Attie, Alan D. / Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. In: Nature genetics. 2006 ; Vol. 38, No. 6. pp. 688-693.
@article{cfd91227f2d44131b938af273b531fd0,
title = "Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus",
abstract = "We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.",
author = "Clee, {Susanne M.} and Yandell, {Brian S.} and Schueler, {Kathryn M.} and Rabaglia, {Mary E.} and Richards, {Oliver C.} and Raines, {Summer M.} and Kabara, {Edward A.} and Klass, {Daniel M.} and Mui, {Eric T.K.} and Stapleton, {Donald S.} and Gray-Keller, {Mark P.} and Young, {Matthew B.} and Stoehr, {Jonathan P.} and Hong Lan and Igor Boronenkov and Phil Raess and Flowers, {Matthew T.} and Attie, {Alan D.}",
year = "2006",
month = "6",
day = "1",
doi = "10.1038/ng1796",
language = "English (US)",
volume = "38",
pages = "688--693",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus

AU - Clee, Susanne M.

AU - Yandell, Brian S.

AU - Schueler, Kathryn M.

AU - Rabaglia, Mary E.

AU - Richards, Oliver C.

AU - Raines, Summer M.

AU - Kabara, Edward A.

AU - Klass, Daniel M.

AU - Mui, Eric T.K.

AU - Stapleton, Donald S.

AU - Gray-Keller, Mark P.

AU - Young, Matthew B.

AU - Stoehr, Jonathan P.

AU - Lan, Hong

AU - Boronenkov, Igor

AU - Raess, Phil

AU - Flowers, Matthew T.

AU - Attie, Alan D.

PY - 2006/6/1

Y1 - 2006/6/1

N2 - We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.

AB - We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.

UR - http://www.scopus.com/inward/record.url?scp=33745260655&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745260655&partnerID=8YFLogxK

U2 - 10.1038/ng1796

DO - 10.1038/ng1796

M3 - Article

VL - 38

SP - 688

EP - 693

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -