Hutchinson-Gilford Progeria. Miranda Lange Biol 409. Introduction & Background. There are a wide range of progeroid syndromes: “ Unimoidal Progeroid’s ” - only impact a single tissue. For Example: Alzheimers: it only impacts the brain tissue.
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Fig. A 1. Radiograph of the chest demonstrates hypoplasia of the clavicles.
2. Radiograph of the pelvis demonstrates bilateral hip dysplasia and coxa valga (hip abnormalities).What is it?
Eriksson, et al. (2003). Nature, Vol. 423, p. 293-297
The boxed interval is the region in proband C8803 that has been inherited exclusively from the mother. NA = not available.
FISH analysis of a metaphase spread from C8803 fibroblasts, hybridized with BAC probes RP11-110J1 (green) and RP11-91G5 (red).
Summary map of the candidate region. Microsatellite markers are indicated with arrows; horizontal bars indicate BAC probes that were used for FISH on sample C8803. LMNA is one of the approximately 80 known genes in the 4.82-Mb candidate interval.
Fig. 3. Representation of LMNA and Lamin A as blue and red colors, respectively. The deleted LMNAtranscript junction sequence is shown as a 150 bp deletion extending from G1819 to the exon 11 end (black box) and is indicated by a black bar in the Lamin A tail. The CaaX-box motif (cysteine-aliphatic-aliphatic-any amino acid) at the C terminus is subject to farnesylation (2).
Eriksson, et al. (2003). Nature, Vol. 423, p. 293-297Exons & Introns
Point mutations in exon 11 of LMNA cause HGPS. Sequence traces from a normal control and two HGPS patients with heterzygous base substitutions, one within the same codon (G608S(GGC . AGC)), and the other within exon 2 (E145K(GAG . AAG)).
How do these de novo mutations cause HGPS?
Demonstration of the abnormal splice product using RT–PCR, showing an abnormal product of 489 bp in two HGPS probands due to activation of the cryptic splice site. Alternative lanes to the right lack reverse transcriptase.
Eriksson, et al. (2003). Nature, Vol. 423, p. 293-297Figure 5,a.
Western blot using a monoclonal antibody against lamin A/C. Lanes 1, 5, 8 and 9 are from AG03506, AG03344, AG11498 and AG01972; all carry G608G(GGC . GGT). Lane 4 is from AG10801, carrying G608S(GGC . AGC); lanes 2 and 3 are from parents of AG03506; lanes 6 and 7 are from father of AG03259 and mother of AG06917, respectively. Lanes 1–5 are from lymphoblastoid cell lines; lanes 6–9 are from fibroblasts. A protein sample from HeLa cells is in lane 10.
Eriksson, et al. (2003). Nature, Vol. 423, p. 293-297Figure 5,b.
Chromosome 1 with Reduction to Homozygosity of the LAMB3 Locus in a Patient with Herlitz Junctional Epidermolysis Bullosa. Am. J. Hum. Genet., Vol. 61, p. 611–619