Hutchinson-Gilford Progeria Syndrome Genetics

Hutchinson-Gilford Progeria Syndrome Genetics Progeria is a rare, fatal, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription. Mutations in the Lamin A: To date, models have been proposed to explain how mutations in the lamin A gene could lead to HGPS, structural fragility and altered gene expression. One model links HGPS to stem cell-driven tissue regeneration. In this model, nuclear fragility of lamin A-deficient cells increases apoptotic cell death to levels that exhaust tissues ability for stem cell-driven regeneration. Tissue-specific differences in cell death or regenerative potential, or both, result in the tissue-specific segmental aging pattern seen in HGPS. Children born with HGPS typically appear normal at birth, but within a year they begin to display the effects of accelerated aging. Typical facial features include micrognathia (small jaw), craniofacial disproportion, alopecia (loss of hair), and prominent eyes and scalp veins. Children experience delayed growth and are short in stature and below average weight. Due to a lack of subcutaneous fat, skin appears wrinkled and aged looking. Other key abnormalities include delayed dentition, a thin and high pitched voice, a pyriform (pear-shaped) thorax, and a horse riding stance. As they mature, the disorder causes children to age about a decade for every year of their life. This means that by the age of 10, an affected child would have the same respiratory, cardiovascular, and arthritic conditions as a senior citizen. On average, death occurs at the age of 13. HGPS vs. Inheritance HGPS had been proposed to be a recessive disorder due to observations of affected individuals found in consanguineous families. However, many cases of progeria were also observed in families in which the parents were not related, suggesting sporadic autosomal dominant inheritance, which has been confirmed with the discovery of the causative mutations. Others have reported the presence of various chromosomal abnormalities, such as an inverted insertion in the long arm of chromosome 1, as possible contributing factors to the disease. These cytogenetic clues proved to be critical for discovery of the HGPS gene. HGPS vs. Genetics After many years of appreciating that HGPS was caused by genetic rather than by environmental factors, researchers took the first steps in isolating genetic mutations that cause HGPS. A team centered at the National Human Genome Research Institute in Maryland, under the direction of Francis Collins, initiated their search with a genome-wide scan. Using 403 polymorphic microsatellite markers, the investigators found no evidence of homozygosity in 12 individuals with classical HGPS. However, two individuals showed uniparental isodisomy of chromosome 1q, and one had a 6Mb paternal interstitial deletion in 1q. From this observation, the investigators concluded that the HGPS gene must lie within a 4.82Mb region on chromosome 1q. This region contains approximately 80 known genes, including Lmna. Lmna and Types A-type and B-type lamins (Type V intermediate filaments) are the main components of the nuclear lamina, the innermost layer of the nuclear envelope. The nuclear lamina in mammalian cells is a thin (20-50 nm) protein meshwork that interacts with various proteins and chromatin and is essential for maintaining the structural integrity of the nuclear envelope, the protective barrier between the cytoplasm and nucleus. Cell studies of HGPS patients Immunofluorescence studies with antibodies against lamin A/C were performed using fibroblasts from HGPS subjects and their parents. The results showed structural nuclear abnormalities in 48% of HGPS cells compared with