MAFB – Duane Retraction Syndrome

MAFB encodes a basic leucine zipper transcription factor critical for the development of podocytes, abducens neurons, and inner ear structures. Duane Retraction Syndrome is characterized by impaired horizontal eye movement due to abducens nerve hypoplasia, often accompanied by hearing impairment. The association of MAFB with Duane Retraction Syndrome was first described in two unrelated families presenting a syndromic form with early-onset focal segmental glomerulosclerosis (FSGS) and Duane anomalies.

In the initial report, four affected individuals across two pedigrees exhibited heterozygous p.Leu239Pro substitution in MAFB, consistent with autosomal dominant inheritance (PMID:29779709). Segregation analysis demonstrated co-segregation of the variant with disease in both families, affecting two additional relatives beyond the index cases. No alternative pathogenic variants were identified in known FSGS or Duane-associated genes.

Functional studies in cultured monocytes showed that p.Leu239Pro significantly reduced transactivation of the MAFB recognition element in the F4/80 promoter, indicating loss of transcriptional activity (PMID:29779709). Immunohistochemistry of patient kidney biopsies revealed decreased MAFB expression in glomerular podocytes, supporting a pathogenic mechanism via impaired target gene regulation.

A humanized mouse model harboring the p.Leu239Pro variant recapitulated key features of the human syndrome: mice displayed podocyte differentiation defects and cranial nerve malformation analogous to Duane-like eye movement restriction (PMID:31882119). These in vivo data confirm that the variant disrupts MAFB function during organogenesis.

Mechanistically, structural modeling suggests that substitution of leucine by proline at residue 239 perturbs the DNA-binding domain adjacent to a zinc finger, likely destabilizing MAFB–DNA interactions. Concordant genetic, in vitro and in vivo evidence supports a dominant-negative or haploinsufficiency mechanism.

Key Take-home: Heterozygous MAFB p.Leu239Pro is a well-validated cause of autosomal dominant Duane Retraction Syndrome with renal involvement, enabling precise molecular diagnosis and genetic counseling.

References

• Kidney international • 2018 • A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome. PMID:29779709
• Biochemical and biophysical research communications • 2020 • Phenotypic analysis of mice carrying human-type MAFB p.Leu239Pro mutation. PMID:31882119

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