Premature Aging

Syndromes
By Kuan-Lin Chu and Nizamuddin Girach
Hutchinson-Gilford Progeria Syndrome
(HGPS)
● Premature aging in childhood
● Infants usually appear normal at birth but profound failure to thrive occurs in the first year
○ Symptoms start to develop during the first year
● Symptoms include
○ Severe atherosclerosis within the during childhood
○ ‘Strawberry chin’ - receded mandible (micrognathia)
○ Alopecia
○ Narrow nasal bridge, and pointed nasal tip
○ Loss of subcutaneous fat
● Mental and motor development is normal
● Average lifespan is 14 years old
○ Death usually as a result of complications due to heart disease
Cause

● De-novo mutation of the LMNA gene with autosomal dominance

● LMNA gene codes for a protein called Lamin A

HGPS -->
Lamin A

● Intermediate filament protein of the nuclear membrane

● Functions include -
○ Regulating nuclear morphology and integrity
○ DNA repair
○ Regulation of gene expression
○ Telomere stability
● LMNA gene codes for 4 types of lamins (A, C, CΔ10, and C2)
○ Via alternative splicing
○ A and C are most expressed
● Mutated Lamin A is called Progerin
 Post Translation
Modifications
to produce Lamin A
Farnesylation = addition of hydrophobic molecule
(isoprenyl group) to a cysteine residue

These modifications allow Prelamin A to associate with

the nuclear envelope

They are then cleaved off as they are not needed

anymore
Mutation of the LMNA gene

● To date there have been over 400 mutations found

● Most famous is the c.1824 C>T transition - A single base substitution in exon
11
● This activates a so called cryptic splice site near the end of the molecule
○ Allows spliceosome to interact with the molecule
○ Results in a 50 amino acid in frame deletion
● Results in the mutation form of Lamin A called Progerin
Diagnosis, management and Genetic
Counselling
● Diagnosis via apparent symptoms, and confirmed via detection of mutation in the LMNA gene at
exon 11
● Treatment - treatment of manifestations,
○ so controlled diet,
○ treating the abnormal atherosclerosis
● Experimental treatment in mice for FarnesylTransferase has proven effective
● Regular heart examinations should be given to monitor heart disease
● Genetic counselling - since almost all mutations are de novo risk for future siblings is very low
Werner syndrome
● Adult progeria - a rare progressive disorder that
is characterized by the appearance of unusually
accelerated aging
● Affected Populations
○ males and females in equal numbers
○ one to 20 per one million individuals in
the United States
● absence of the growth spurt typically seen
during adolescence
● Before age 20, most individuals with Werner
syndrome develop early graying and whitening
of the scalp hair
● By about 25 years of age, affected individuals
may experience premature loss of scalp hair
(alopecia)
Clinical symptoms
● In addition to premature graying and hair loss, individuals with Werner syndrome are affected by other
progressive degenerative changes
○ gradual loss of the layer of fat beneath the skin (subcutaneous adipose tissue)
○ severe wasting (atrophy) of muscles within the hands, legs, and feet
○ premature loss of bone density (osteoporosis)
○ premature onset of senile cataracts, a condition in which there is loss of transparency of the
lenses of the eyes
● Approximately 70 percent of affected individuals have develop non-insulin-dependent (or type II)
diabetes mellitus at the time of diagnosis
● Werner syndrome is also characterized by severe, progressive, often widespread thickening and loss
of elasticity of artery walls (arteriosclerosis)
● People with Werner syndrome also have an increased predisposition to cancers
○ carcinomas of thyroid, malignant melanoma
Causes
● mutations in the WRN gene
○ chromosome 8
○ WRN gene consists of 35
exons that encode a protein of
1,432 amino acids
○ RecQ-type helicase domains
in the central region
○ exonuclease domains in the N-
terminal region
○ nuclear localization signal is
present at the C-terminal
region
● involved in DNA replication, repair,
recombination, transcription, telomere
maintenance and DNA repair
pathway
DNA repair pathway
● nonhomologous chromosome exchanges,
termed variegated translocation mosaicism
● loss in the fidelity of repairing DNA double
strand breaks (DSB)
● DSB are repaired either by non-homologous
end joining (NHEJ) or homologous
recombination (HR)
Mutation of WRN
● during laboratory (in vitro) studies of samples of
cultured human fibroblasts, researchers have
demonstrated that the cells from individuals without
the disorder may multiply approximately 60 times
whereas Werner syndrome fibroblasts may
reproduce only up to about 20 times.
● regulate the total number of times that human cells
may divide and reproduce
● premature inhibition of DNA replication processes
and early cellular aging
● Defect in telomere metabolism
Diagnosis, management and Genetic
Counselling
● may not be recognized or confirmed until the third or fourth decades of life, once certain distinctive
symptoms and findings are noted
● Confirmation may be achieved by molecular testing of the WRN gene
● Treatment is directed toward the specific symptoms that are apparent in each individual
● Genetic counseling is recommended for individuals with Werner syndrome and their families
○ autosomal recessive
○ the parents of some individuals with Werner syndrome have been closely related by blood