PMID- 19720790
OWN - NLM
STAT- MEDLINE
DCOM- 20091214
LR  - 20230519
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 58
IP  - 12
DP  - 2009 Dec
TI  - Severe insulin resistance and intrauterine growth deficiency associated with 
      haploinsufficiency for INSR and CHN2: new insights into synergistic pathways 
      involved in growth and metabolism.
PG  - 2954-61
LID - 10.2337/db09-0787 [doi]
AB  - OBJECTIVE: Digenic causes of human disease are rarely reported. Insulin via its 
      receptor, which is encoded by INSR, plays a key role in both metabolic and growth 
      signaling pathways. Heterozygous INSR mutations are the most common cause of 
      monogenic insulin resistance. However, growth retardation is only reported with 
      homozygous or compound heterozygous mutations. We describe a novel translocation 
      [t(7,19)(p15.2;p13.2)] cosegregating with insulin resistance and pre- and 
      postnatal growth deficiency. Chromosome translocations present a unique 
      opportunity to identify modifying loci; therefore, our objective was to determine 
      the mutational mechanism resulting in this complex phenotype. RESEARCH DESIGN AND 
      METHODS: Breakpoint mapping was performed by fluorescence in situ hybridization 
      (FISH) on patient chromosomes. Sequencing and gene expression studies of 
      disrupted and adjacent genes were performed on patient-derived tissues. RESULTS 
      Affected individuals had increased insulin, C-peptide, insulin-to-C-peptide 
      ratio, and adiponectin levels consistent with an insulin receptoropathy. FISH 
      mapping established that the translocation breakpoints disrupt INSR on chromosome 
      19p15.2 and CHN2 on chromosome 7p13.2. Sequencing demonstrated INSR 
      haploinsufficiency accounting for elevated insulin levels and dysglycemia. CHN2 
      encoding beta-2 chimerin was shown to be expressed in insulin-sensitive tissues, 
      and its disruption was shown to result in decreased gene expression in 
      patient-derived adipose tissue. CONCLUSIONS: We present a likely digenic cause of 
      insulin resistance and growth deficiency resulting from the combined heterozygous 
      disruption of INSR and CHN2, implicating CHN2 for the first time as a key element 
      of proximal insulin signaling in vivo.
FAU - Suliman, Sara G I
AU  - Suliman SG
AD  - Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, 
      Oxford, U.K.
FAU - Stanik, Juraj
AU  - Stanik J
FAU - McCulloch, Laura J
AU  - McCulloch LJ
FAU - Wilson, Natalie
AU  - Wilson N
FAU - Edghill, Emma L
AU  - Edghill EL
FAU - Misovicova, Nadezda
AU  - Misovicova N
FAU - Gasperikova, Daniela
AU  - Gasperikova D
FAU - Sandrikova, Vilja
AU  - Sandrikova V
FAU - Elliott, Katherine S
AU  - Elliott KS
FAU - Barak, Lubomir
AU  - Barak L
FAU - Ellard, Sian
AU  - Ellard S
FAU - Volpi, Emanuela V
AU  - Volpi EV
FAU - Klimes, Iwar
AU  - Klimes I
FAU - Gloyn, Anna L
AU  - Gloyn AL
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - G0700222/MRC_/Medical Research Council/United Kingdom
GR  - G0700222(81696)/MRC_/Medical Research Council/United Kingdom
GR  - 81696/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090831
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Antigens, CD)
RN  - 0 (Biomarkers)
RN  - 0 (Blood Glucose)
RN  - 0 (C-Peptide)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Insulin)
RN  - 0 (NR4A3 protein, human)
RN  - 0 (Receptors, Steroid)
RN  - 0 (Receptors, Thyroid Hormone)
RN  - EC 2.7.10.1 (INSR protein, human)
RN  - EC 2.7.10.1 (Receptor, Insulin)
SB  - IM
MH  - Adult
MH  - Age of Onset
MH  - Antigens, CD/*genetics
MH  - Biomarkers/blood
MH  - Blood Glucose/metabolism
MH  - C-Peptide/blood
MH  - Chromosome Mapping
MH  - Chromosomes, Human, Pair 19
MH  - Chromosomes, Human, Pair 7
MH  - DNA-Binding Proteins/*genetics
MH  - Diabetes Mellitus/*genetics/metabolism
MH  - Female
MH  - Fetal Growth Retardation/*genetics/metabolism
MH  - Gene Expression Regulation
MH  - Growth Disorders/*genetics/metabolism
MH  - Haplotypes
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Insulin/blood/*metabolism
MH  - *Insulin Resistance
MH  - Male
MH  - Pregnancy
MH  - Receptor, Insulin/*genetics
MH  - Receptors, Steroid/*genetics
MH  - Receptors, Thyroid Hormone/*genetics
MH  - Sequence Analysis, DNA
MH  - Signal Transduction
MH  - Translocation, Genetic
PMC - PMC2780873
EDAT- 2009/09/02 06:00
MHDA- 2009/12/16 06:00
PMCR- 2010/12/01
CRDT- 2009/09/02 09:00
PHST- 2009/09/02 09:00 [entrez]
PHST- 2009/09/02 06:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
PHST- 2010/12/01 00:00 [pmc-release]
AID - db09-0787 [pii]
AID - 0787 [pii]
AID - 10.2337/db09-0787 [doi]
PST - ppublish
SO  - Diabetes. 2009 Dec;58(12):2954-61. doi: 10.2337/db09-0787. Epub 2009 Aug 31.