HMX1 – Oculoauricular Syndrome

HMX1 is a homeobox transcription factor essential for ocular and auricular development. Biallelic loss-of-function variants in HMX1 underlie autosomal recessive oculoauricular syndrome (OAS), characterized by congenital cataract, anterior segment dysgenesis, iris coloboma, microcornea, microphthalmia, early-onset retinal dystrophy, and external ear malformations.

Genetic evidence comprises two independent families: a consanguineous pedigree with two affected siblings homozygous for c.650A>C (p.Gln217Pro) (PMID:25574057), and a non-consanguineous family with one proband homozygous for c.487G>T (p.Glu163Ter) (PMID:29140751). Both variants are absent from population controls and affect the conserved homeodomain or introduce a premature stop codon.

Segregation is documented in the consanguineous family, where homozygosity co-segregates with disease in two siblings and parents are heterozygous carriers, yielding one additional affected relative (PMID:25574057).

Functional assays demonstrate that p.Gln217Pro disrupts protein folding and impairs transcriptional activity without altering expression, as shown by protein modelling, Western blotting, and dual luciferase reporter assays (PMID:25574057). These data support a loss-of-function mechanism.

In mouse models, predictive promoter modeling and transcriptomic analysis in Hmx1-null retinas identify target genes in retinal axon guidance, and serial promoter deletions confirm critical regulatory elements governing Nkx5-3 expression (PMID:23946633; PMID:18258389).

Collectively, genetic and experimental data support a Moderate level of clinical validity for HMX1 in OAS. Inclusion of HMX1 in diagnostic gene panels for congenital cataract and anterior segment dysgenesis is warranted. Key take-home: HMX1 loss-of-function variants cause autosomal recessive oculoauricular syndrome and should be considered in early-onset ocular and auricular anomalies.

References

• Investigative ophthalmology & visual science • 2015 • Abrogation of HMX1 function causes rare oculoauricular syndrome associated with congenital cataract, anterior segment dysgenesis, and retinal dystrophy. PMID:25574057
• Ophthalmic genetics • 2018 • Further delineation of the oculoauricular syndrome phenotype: A new family with a novel truncating HMX1 mutation. PMID:29140751
• Molecular vision • 2013 • Identification of HMX1 target genes: a predictive promoter model approach. PMID:23946633
• Gene • 2008 • Identification of the minimal promoter region of the mouse NKX5-3, a transcription factor implicated in eye development. PMID:18258389

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