Maternal nutrition determines the variable expressivity of STRA6-associated eye malformations.

Abstract

Mutations in <i>STRA6</i>, the high-affinity receptor for retinol-binding protein, cause Matthew-Wood syndrome, a congenital disorder characterized by striking phenotypic variability ranging from isolated ocular anomalies to severe multisystem malformations. The mechanisms underlying this variable expressivity and incomplete penetrance remain poorly understood. Here, we used mice to determine how maternal vitamin A status and embryonic <i>Stra6</i> genotype interact to shape ocular development. Using <i>Stra6</i>-deficient mice bred under defined dietary conditions, we demonstrate that maternal vitamin A availability is a major modifier of phenotypic outcome. Maternal vitamin A restriction resulted in microphthalmia and markedly reduced postnatal survival of the offspring. Remarkably, offspring of <i>Stra6</i>^-/- dams maintained on a vitamin A-sufficient diet, corresponding to the recommended dietary allowance for mice, also developed pronounced ocular abnormalities, including retinal dysplasia and impaired rod and cone opsin differentiation. In contrast, supraphysiological maternal vitamin A intake, as provided by a standard chow, partially rescued ocular development and produced near-normal eye morphology in the offspring. Strikingly, heterozygous <i>Stra6</i>^+/- offspring born to <i>Stra6</i>^-/- dams were protected from both lethality and ocular malformations despite maternal STRA6 deficiency and dietary vitamin A restriction. Biochemical analyses revealed that ocular retinoid availability strictly depended on the <i>Stra6</i> genotype of the offspring, whereas some circulating retinol remained detectable even under maternal vitamin A deficiency. Together, these findings identify a gene-nutrient interaction that explains the variable expressivity of <i>STRA6</i>-associated disease and establish maternal vitamin A status as a critical determinant of ocular development and postnatal survival.