Download Role of Spirometry and Exhaled Nitric Oxide To Predict

Clinical and Molecular Genetic Spectrum
of
Congenital Deficiency of the Leptin
Receptor
I. Sadaf Farooqi, M.B., B.S., Ph.D., Teresia Wangensteen,
M.D., Stephan Collins, Ph.D., Wendy Kimber, Ph.D.,
Giuseppe Matarese, M.D., Ph.D., et al.
N Engl J Med Jan.18, 2007;356;3
R2. Hwang Seung-Joon
Background (1)
◆Severe early-onset obesity
-Classically, assess the neurologic, endocrinologic,
genetic condition
-Several monogenic disorders
: Obesity itself is the predominant presenting
feature
Disruption of the hypothalamic leptin –
melanocortin signaling pathway
Background (2)
-12 subjects with congenital leptin deficiency due to
loss-of-function mutations in the gene encoding
leptin have been identified
-Only 1 mutation in the leptin-receptor gene (LEPR)
has been reported, in 3 severely obese adult siblings
from a consanguineous family of Algerian origin
-Studied 300 subjects with severe, early-onset obesity
Methods (1)
●Subjects
“Genetics of Obesity Study (GOOS) cohort”
: 2100 unrelated probands with severe obesity of early
onset (before 10 years of age)
300 were selected to determine the prevalence of
leptin receptor mutations
-Mean BMI standard-deviation score for the
group screened : 4.5±1.2
-SIM1, NHLH2, CPE, MCHR1, MCHR2 : No mutations
Methods (2)
●Detection of Mutations and Genotyping
-Genomic DNA was isolated from leukocytes derived
from whole blood
-Coding region of the LEPR gene was amplified with
the use of the PCR and was then sequenced
-Also sequenced LEPR gene in impartially selected
nonobese control subjects
-100 alleles from each of 3 population-derived cohorts
: White European origin, South Asian origin, Turkish
origin
Methods (3)
●Body Composition, Growth, and Energy Balance
-Body composition
: Anthropometric methods & Whole-body dual-energy
x-ray absorptiometry
-Resting metabolic rate
: Indirect calorimetry after 12hr-overnight fasting
●Metabolic & Endocrine status
-Fasting blood samples
leptin, glucose, insulin, thyrotropin, free thyroxine,
insulin-like growth factor 1 (IGF-1), folliclestimulating hormone, luteinizing hormone, estradiol,
testosterone
Methods (4)
●Lymphocyte count & Function
-Lymphocytes Isolation
-Cell phenotypes : Measured by cytofluorometric analysis
-Lymphocyte counts & Proliferative responses in
subjects with leptin-receptor deficiency
(Vs. 46 control subjects matched for age)
●Statistical Analysis
-Expression : Means ± SD
-unpaired Student’s t-test
-P value : two-sided tests
(Statistical significance : p <0.05)
Results
Detection of Mutations and Family Studies
Pedigrees of Consanguineous Families with Mutations
in the Leptin-Receptor Gene (1)
Pedigrees of Consanguineous Families with Mutations
in the Leptin-Receptor Gene (2)
Pedigrees of Nonconsanguineous Families with Mutations
in the Leptin-Receptor Gene
Mutations in the Leptin-Receptor Gene
Functional Analysis of Mutant Receptors
A409E, W664R, H684P : Complete loss of
signaling
R612H : Some residual ability to phosphorylate
STAT3 in response to leptin
Clinical phenotype for Leptin receptor deficiency
-LEPR mutation group (10)
VS
-Congenital leptin deficiency group (5)
VS
-MC4R (Melanocortin 4 receptor) mutation group (5)
Body composition & Energy balance
Metabolic & Endocrine function
Immune function
Body composition and Energy balance
Metabolic and Endocrine function
Immune function
●Leptin-receptor deficient subject
: Marked reduction in the CD4+ T-cell count
& Reduced T-cell proliferation
-Leptin-receptor–deficient subjects
(mean, 988±186 cells / mm3 ; 42±13%)
-Control subjects
(mean, 1100±892 cells / mm3 ; 44±7%)
Conclusions
●LEPR mutation
: Hyperphagia, Severe obesity, Alterations
in immune function, Delayed puberty
due to hypogonadotropic-hypogonadism
: Should be considered in the differential
diagnosis in any child with hyperphagia and
severe obesity in the absence of
developmental delay or dysmorphism