AP1B1 – MEDNIK syndrome

MEDNIK syndrome is an autosomal recessive disorder characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma. Classically caused by bi-allelic variants in AP1S1, recent evidence implicates AP1B1 in a MEDNIK-like phenotype with overlapping clinical and biochemical features. The identification of AP1B1 expands copper metabolism disorders and informs diagnostic testing for patients presenting with this multisystemic syndrome.

Genetic evidence for AP1B1 involvement arises from three affected individuals in two unrelated consanguineous families who harbor homozygous loss-of-function variants in AP1B1. The sole reported variant, c.38-1G>A, disrupts canonical splicing of exon 2 in AP1B1 and segregates with disease in all affected members (PMID:31630791).

Inheritance is autosomal recessive, with homozygous null alleles observed in each proband. Segregation analysis across two families demonstrated cosegregation of the c.38-1G>A allele with affected status, including one additional affected sibling, supporting pathogenicity under a recessive model (PMID:31630791).

To date, only loss-of-function variants in AP1B1 have been reported in MEDNIK-like cases; no missense or hypomorphic alleles have been described. The recurrent intronic splice-site change appears private to these pedigrees, with no founder or population-specific alleles identified to date.

Functional studies using patient-derived fibroblasts demonstrate abnormal AP-1–mediated trafficking of the copper transporter ATP7A both at baseline and upon copper challenge, phenocopying the cellular defect seen in AP1S1-related MEDNIK syndrome. These assays confirm a loss-of-function mechanism resulting in perturbation of copper homeostasis (PMID:31630791).

In summary, AP1B1 loss-of-function variants cause a MEDNIK-like syndrome with consistent clinical, biochemical, and cellular features mirroring AP1S1-related disease. AP1B1 should be included in gene panels for inborn errors of copper metabolism and syndromic ichthyosis with neurodevelopmental involvement. Key Take-home: Bi-allelic AP1B1 LoF screening refines diagnosis and enables targeted management in MEDNIK-spectrum disorders.

References

• American journal of human genetics • 2019 • Homozygous Loss-of-Function Mutations in AP1B1, Encoding Beta-1 Subunit of Adaptor-Related Protein Complex 1, Cause MEDNIK-like Syndrome. PMID:31630791

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