Meet Sam, A Rapidly Aging Child

Classical Hutchinson–Gilford Progeria Syndrome (HGPS) is a rare genetic disorder of accelerated aging, caused by a de novo point mutation in the LMNA gene. This case explores the underlying causes of HGPS, through the story of Sampson "Sam" Gordon Berns. The primary molecule studied in this case is the LMNA gene product - Lamin A/C, an intermediate-filament protein that forms the meshwork beneath the inner nuclear membrane. The case examines the classic mutation that leads to Sam's condition, and then the structures of two more mutants, one that adds an abnormal hydrophobic patch to the lamin rod (S143F), and one that removes a stabilizing salt bridge from the Ig-like fold (R527L). Comparing these structures illustrate how the same protein can fail through three very different molecular mechanisms in three different domains. The case is structured in five sequential parts that build from clinical observation (Part 1) through molecular mechanism (Parts 2–3), cellular consequence (Part 4), and therapeutic strategy (Part 5). Each part contains one or more graded question blocks and, where appropriate, a summative "hook" question intended as a synthesis checkpoint.