ZMPSTE24 – Mandibuloacral Dysplasia

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome characterized by mandibular and clavicular hypoplasia, acro-osteolysis, delayed cranial suture closure, lipodystrophy, and cutaneous atrophy. MAD can result from biallelic mutations in LMNA or in ZMPSTE24, a zinc metalloproteinase required for post-translational processing of prelamin A into mature lamin A (ZMPSTE24; Mandibuloacral Dysplasia).

Genetic studies have identified at least 6 unrelated MAD patients harboring compound heterozygous or homozygous ZMPSTE24 variants, consistent with autosomal recessive inheritance and segregation in families (PMID:20814950). The most recurrent alleles include c.743C>T (p.Pro248Leu) and c.1349G>A (p.Trp450Ter), with functional null or hypomorphic effects. Segregation analysis demonstrated that parents and unaffected siblings are heterozygous carriers without clinical manifestations.

The variant spectrum comprises missense (e.g., c.743C>T (p.Pro248Leu)), nonsense (c.202C>T (p.Arg68Ter)), frameshift (c.1085dup (p.Leu362fsTer379)), and splice-site mutations, all leading to deficient ZMPSTE24 activity in prelamin A cleavage. One representative allele used in diagnostic panels is c.1018T>C (p.Trp340Arg), which abolishes metalloprotease function in yeast assays.

Functional assays in yeast complementation models confirmed that frameshift and missense ZMPSTE24 mutants (e.g., Phe361fsX379/inactive; Trp340Arg/partial activity) fail to process prelamin A, recapitulating MAD cellular phenotypes (PMID:12913070). Zmpste24-deficient mice accumulate prelamin A, exhibit nuclear shape abnormalities and progeroid features, and display upregulated p53 target genes, establishing a mechanistic link between ZMPSTE24 deficiency and premature aging (PMID:11399759).

Clinically, MAD due to ZMPSTE24 mutations presents in infancy or early childhood with thin skin, large fontanelles, osteolytic phalangeal defects, micrognathia, joint stiffness, and progressive lipodystrophy. Compared to LMNA-related MAD, ZMPSTE24-linked cases often show earlier onset of skeletal manifestations and occasional renal involvement.

Integration of genetic and functional data supports a Strong gene-disease association. Genetic testing of ZMPSTE24 in patients with suspected MAD is warranted to confirm diagnosis, guide family counseling, and inform potential therapeutic approaches targeting farnesylation or proteostasis.

Key Take-home: Biallelic ZMPSTE24 mutations cause autosomal recessive mandibuloacral dysplasia via impaired prelamin A processing, underpinning clinical utility of genetic testing in early-onset progeroid syndromes.

References

• Human molecular genetics • 2003 • Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. PMID:12913070
• American journal of medical genetics. Part A • 2010 • Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24. PMID:20814950
• Journal of biological chemistry • 2001 • Biochemical studies of Zmpste24-deficient mice. PMID:11399759

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