ZMPSTE24 – Restrictive Dermopathy

ZMPSTE24 encodes a zinc metalloprotease essential for the final endoproteolytic cleavage of farnesylated prelamin A to yield mature lamin A. Biallelic loss-of-function variants in ZMPSTE24 result in the lethal genodermatosis restrictive dermopathy (RD; [MONDO:0031213]), which presents perinatally with tight, translucent skin and early neonatal death ([PMID:15317753]).

Genetic evidence for ZMPSTE24 in RD is definitive by ClinGen standards. Over 60 unrelated RD patients have been reported with homozygous or compound heterozygous ZMPSTE24 null alleles in multiple series spanning >15 years ([PMID:20101687]). The autosomal recessive inheritance is confirmed by parental carrier status and recurrence in siblings across at least 7 families ([PMID:15843403]).

The variant spectrum is dominated by frameshift insertions and deletions and essential splice-site mutations leading to premature truncation or exon skipping. Recurrent variants include c.50del (p.Lys17SerfsTer21) and c.1085dup (p.Leu362PhefsTer19), both located in exon 9, with no consistent founder effect across populations ([PMID:20101687]).

Clinically, RD is characterized by intrauterine growth retardation (HP:0001511), taut, easily eroded skin with prominent superficial vessels (HP:0007394), multiple joint contractures (HP:0002828), and a fixed “O”-shaped mouth with pinched facial features (HP:0001999). Pulmonary hypoplasia and epidermal hyperkeratosis further define the phenotype, with affected neonates invariably dying within the first days of life ([PMID:15317753]).

Functional studies demonstrate that ZMPSTE24 deficiency leads to accumulation of unprocessed prelamin A, absence of mature lamin A, and profound nuclear envelope disorganization in patient cells and Zmpste24–/– mice. These defects recapitulate the human RD phenotype, establishing loss of ZMPSTE24 proteolytic activity as the disease mechanism ([PMID:15317753]; [PMID:15843403]).

Integrated evidence establishes a definitive gene–disease relationship with strong genetic and experimental concordance. Comprehensive ZMPSTE24 sequencing is essential for confirming RD diagnosis, guiding prognostic counseling, and enabling reproductive planning.

Key take-home: ZMPSTE24 biallelic null mutations cause autosomal recessive restrictive dermopathy, a neonatal lethal laminopathy diagnosable by targeted genetic testing.

References

• Human molecular genetics • 2004 • Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. PMID:15317753
• Human molecular genetics • 2005 • Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors. PMID:15843403
• The Journal of investigative dermatology • 2005 • Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy. PMID:16297189
• American journal of medical genetics. Part A • 2010 • Novel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literature. PMID:20101687

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