Hutchinson-Gilford Progeria Syndrome Genetics
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Published: Wed, 16 May 2018
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 <6% of normal control cells. Additional analyses described HGPS lymphocytes as having ‘strikingly altered nuclear sizes and shapes, with envelope interruptions accompanied by chromatin extrusion’. Lamin A expression in HGPS lymphocytes was only 25% of that from normal controls. In more recent studies, Bridger and Kill have observed that HGPS fibroblasts undergo a period of hyperproliferation followed by rapid apoptotic death. These experiments are starting to clarify cellular processes in premature aging due to mutant Lmna.
Werner’s syndrome Vs. HGPS
Werner’s syndrome (WRN; MIM 277700) is another progeroid syndrome. Later onset, skin calcification, cataracts, and cancer susceptibility are a few of the features that distinguish it from HGPS. Mutations for this disease have been found in the WRN gene which encodes WRN protein, a member of the RecQ family of DNA helicases. However, not all individuals diagnosed with WRN carry a mutation in WRN. A subset of these atypical WRN patients, with an earlier mean age of diagnosis than the classical WRN, were shown to actually carry novel mutations in Lmna, namely A57P within the globular head domain and R133L and L140R, both within the alpha-helical coiled coil domain. The diagnosis of these younger WRN patients as having a laminopathic progeria would suggest that they might actually be atypical HGPS rather than atypical WRN. In a recent screening of atypical progeroid patients, three additional novel heterozygous Lmna mutations have been found, namely, R644C affecting the C-terminus in a subject with atypical HGPS, E578V also in the C-terminus in a subject with either severe WRN or mild HGPS, and T10I within the N-terminal globular domain in a patient diagnosed with Seip syndrome. Fibroblasts from these probands contained a large proportion of irregularly shaped nuclei as observed previously in other laminopathies. Hence, Lmna is a good candidate not only for HGPS, but also for atypical progeria. Such findings indicate that molecular diagnosis can help classify subjects with ambiguous or unclear clinical diagnosis. Future treatments may depend on having a precise molecular diagnosis. The recent discovery of Lmna mutations in HGPS provides hope both for the children affected by this disease and for their families. However, a cure is still in the distant future, with much work needed to determine the detailed cellular mechanisms underlying the disease. There are many obstacles hindering the investigation of HGPS. A major hurdle is the small number of individuals affected with HGPS: <40 known cases worldwide at present. The Coriell Cell Repository and the Progeria Research Foundation Cell and Tissue Bank are excellent resources, but still, the numbers of affected subjects are few. In addition, many patients do not have a typical phenotype. There may also be other genetic loci that can modify the HGPS phenotype. Other challenges will lie in determining the most appropriate mouse models.
HGPS VS. Molecular diagnostic
As most cases of HGPS appear to be due to a de novo mutation in the same codon (G608G), screening for this mutation is certainly theoretically feasible, especially with the decreasing cost of genomic DNA analysis. However, due to the sporadic nature of the phenotype, predictive screening is not practical at present, since there is no way to determine which children are at risk. Furthermore, the benefit is limited, considering that there is no present treatment for progeria. For the parents of a previously affected child, parental somatic mosaicism is a theoretical possibility. Concerns about the recurrence of HGPS in future pregnancies for such individuals might now be addressed through genetic testing. Lmna testing may also be valuable in making a molecular diagnosis in an individual affected with a suggestive phenotype, that is, to determine whether their disease was ‘classical’ HGPS or atypical progeroid. As mentioned above, a precise molecular diagnosis may be important, as future therapies may depend upon knowing the genetic basis of the phenotype.
Treatments- Cure- Drugs:
There is no cure for HGPS, but a regular monitoring for cardiovascular disease may be a big help for the child. However there are some therapies that may reduce the symptoms and the signs of HGPS.
Low dose Aspiring, it helps preventing heart attacks/strokes.
High-calorie dietary supplements: help with the loss of weight.
Drugs known as farnesyltransferase inhibitors (FTIs), which were developed for treating cancer, have shown promise in laboratory studies in correcting the cell defects that cause progeria. FTIs are currently being studied in human clinical trials for treatment of progeria.
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