ZMPSTE24 – Mandibuloacral Dysplasia Type B Lipodystrophy

ZMPSTE24 encodes a zinc metalloproteinase responsible for the critical C-terminal cleavage of farnesylated prelamin A to mature lamin A. Pathogenic biallelic variants in ZMPSTE24 cause mandibuloacral dysplasia with type B lipodystrophy (MADB), an autosomal recessive premature aging disorder. Patients exhibit generalized or partial lipodystrophy, atrophic and sclerodermic skin, brittle or sparse hair, and skeletal abnormalities including mandibular and clavicular hypoplasia and acro-osteolysis. Diagnosis relies on molecular confirmation of ZMPSTE24 mutations and characteristic radiological signs such as occipital squama ossification failure.

MADB has been reported in at least 20 individuals from nine unrelated families, including a founder homozygous c.1196A>G (p.Tyr399Cys) variant in eight related patients of Surinamese origin ([PMID:27410998], [PMID:31856865]). A Chilean patient was compound heterozygous for c.1085dup (p.Leu362PhefsTer19) and c.794A>G (p.Asn265Ser) ([PMID:30919593]). More recently, consanguineous families segregating a homozygous frameshift c.28_29insA (p.Leu10TyrfsTer?) variant have been described with an alternative downstream translation initiation rescue mechanism ([PMID:35597529]). These alleles exhibit complete or partial loss of ZMPSTE24 enzyme activity correlating with phenotype severity.

Variants include recurrent missense changes and loss-of-function alleles: c.1196A>G (p.Tyr399Cys) is a population-specific founder variant, c.794A>G (p.Asn265Ser) and c.1085dup (p.Leu362PhefsTer19) occur in compound heterozygotes, and c.28_29insA (p.Leu10TyrfsTer?) highlights the importance of alternative translation initiation in variant interpretation. Segregation analysis demonstrates autosomal recessive inheritance with eight affected relatives in a founder cohort. No dominant-negative or gain-of-function effects have been reported.

Clinically, MADB patients share major criteria such as short stature, mandibular hypoplasia, delayed cranial suture closure, acro-osteolysis, brittle/sparse hair, mottled skin pigmentation, atrophic skin, and calcified skin nodules. Minor features include lipodystrophy pattern variability, ptosis, microcephaly, facial dysmorphism, and novel findings like occipital squama ossification failure that aid radiological diagnosis ([PMID:27410998]).

Functional assays support pathogenicity: Zmpste24 knockout mice accumulate unprocessed prelamin A and recapitulate progeroid and lipodystrophic features. Yeast complementation assays show that frameshift mutations abrogate activity whereas missense alleles retain partial function. In vitro studies demonstrate that residual ZMPSTE24 activity correlates with MADB versus restrictive dermopathy severity ([PMID:12913070], [PMID:22718200]).

No conflicting evidence disputes the ZMPSTE24–MADB association. Integration of genetic and functional data confirms a haploinsufficiency-like mechanism where reduced protease activity leads to toxic prelamin A accumulation. Molecular testing of ZMPSTE24 variants alongside key clinical and radiological signs enables accurate diagnosis, family counseling, and potential enzyme-targeted therapies. Key Take-home: Biallelic ZMPSTE24 mutations causing impaired prelamin A processing are definitively associated with autosomal recessive MADB, and recognition of founder and rescue alleles informs precise genetic diagnosis and management.

References

• American journal of medical genetics. Part A • 2016 • Failure of ossification of the occipital bone in mandibuloacral dysplasia type B. PMID:27410998
• Orphanet journal of rare diseases • 2019 • Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines. PMID:31856865
• American journal of medical genetics. Part A • 2019 • Mandibuloacral dysplasia with type B lipodystrophy in a patient from Chile. PMID:30919593
• Gene • 2022 • An exceptional biallelic N-terminal frame shift mutation in ZMPSTE24 leads to non-lethal progeria due to possible utilization of a downstream alternative start codon. PMID:35597529
• Human molecular genetics • 2003 • Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. PMID:12913070
• Human molecular genetics • 2012 • Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity. PMID:22718200

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