Restrictive Dermopathy 2
In a premature infant (P1) who died at 6 months of age due to restrictive dermopathy (RSDM2; 619793), Navarro et al. (2004) identified a heterozygous G-to-A transition at position 1 in the intron 11 donor site of the LMNA gene (IVS11+1G-A), resulting in loss of exon 11 from the transcript. The patient expressed lamins A and C and a truncated prelamin A. Patient cells showed an abnormal transcript with an in-frame deletion of the entire exon 11 (270 bp), predicted to cause an internal deletion of 90 residues corresponding to a large part of the globular domain (Gly567_Gln656del).
Barthelemy et al. (2015) analyzed LMNA exon 11 transcripts in cells derived from the patient reported by Navarro et al. (2004). In addition to production of a normal full-length prelamin A transcript, there was a band corresponding to prelamin A(del50) (progerin), and an additional transcript correlation to prelamin A(del90) resulting from the skipping of all of exon 11. The prelamin A(del90) transcript was termed 'dermopathin.'
Hutchinson-Guilford Progeria Syndrome
In a patient with an extremely severe form of Hutchinson-Guilford progeria syndrome (HGPS; 176670), Moulson et al. (2007) identified a heterozygous G-to-A transition at the +1 position of the donor splice site of intron 11 in the LMNA gene (1968+1G-A). RT-PCR studies showed a truncated protein product identical to that observed in HGPS cell lines with the common 1824C-T mutation (150330.0022), indicating that the new mutation resulted in the abnormal use of the same cryptic exon 11 splice site. The findings were in contrast to those reported by Navarro et al. (2004), who observed skipping of exon 11 with 1968+1G-A. Further quantitative studies of the patient's cells by Moulson et al. (2007) found a 4.5-fold increase in the relative ratio of mutant mRNA and protein to wildtype prelamin A compared to typical HGPS cells. The findings were confirmed by Western blot analysis and provided an explanation for the severe phenotype observed in this patient. He had had abnormally thick and tight skin observed at 11 weeks of age, and developed more typical but severe progeroid features over time. He died of infection at age 3.5 years.
