LMNA – Hutchinson-Gilford Progeria Syndrome

LMNA encodes the nuclear A-type lamins, critical components of the nuclear lamina. Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare premature aging disorder marked by growth failure, alopecia, lipodystrophy, sclerodermatous skin changes, nail dystrophy and fatal cardiovascular disease. Classical HGPS is caused by autosomal dominant de novo mutations in LMNA, leading to expression of a truncated, farnesylated prelamin A (“progerin”) that disrupts nuclear architecture.

Genetic Evidence

HGPS is inherited in an autosomal dominant manner, typically as de novo events. Eighteen of twenty unrelated classical HGPS probands harbored the identical de novo single-base substitution c.1824C>T (p.Gly608Gly), which activates a cryptic splice donor site and produces progerin ([PMID:12714972]). No familial segregation beyond probands is observed in classical HGPS.

Variant Spectrum

The recurrent synonymous splice-site mutation c.1824C>T (p.Gly608Gly) accounts for >90% of cases, with incomplete RNA splicing leading to a 50–amino-acid deletion in prelamin A. Rare alternative LMNA variants (e.g., c.1821G>A) also activate the same cryptic splice site and produce higher progerin:mature lamin A ratios in severe phenotypes ([PMID:17469202]).

Mechanism of Pathogenicity

Progerin retains its farnesyl‐modified C terminus and cannot undergo normal proteolytic maturation. Progerin incorporates into the nuclear lamina and acts via a dominant-negative mechanism, leading to misshapen nuclei, altered chromatin organization and cellular senescence.

Functional Studies

Primary dermal fibroblasts from HGPS patients expressing progerin exhibit dysmorphic nuclei and hypersensitivity to heat shock ([PMID:15982412]). In a mouse model with osteoblast-specific overexpression of LMNA c.1824C>T, animals display growth retardation, spontaneous fractures, bone mineralization defects and increased DNA damage, mirroring human skeletal abnormalities ([PMID:22893709]). Farnesyltransferase inhibitor treatment partially rescues nuclear shape abnormalities in patient cells ([PMID:17469202]).

Clinical and Diagnostic Utility

Clinical recognition of the characteristic phenotype followed by targeted sequencing of LMNA exon 11 for c.1824C>T enables definitive diagnosis. Early genetic confirmation allows enrollment in clinical trials (e.g., farnesyltransferase inhibitors) and informs prognosis, genetic counseling and prenatal testing.

Key Take-home: De novo LMNA splice-site mutations causing progerin accumulation produce a definitive, autosomal dominant progeroid syndrome with robust genetic and functional evidence, directly informing diagnostic workflows and therapeutic development.

References

• Nature • 2003 • Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. PMID:12714972
• BMC Cell Biology • 2005 • Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress. PMID:15982412
• The Journal of Biological Chemistry • 2012 • Expression of the Hutchinson-Gilford progeria mutation during osteoblast development results in loss of osteocytes, irregular mineralization, and poor biomechanical properties. PMID:22893709
• Human Mutation • 2007 • Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. PMID:17469202

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