Phenotypic spectrum ofSTRA6mutations: from Matthew-Wood syndrome to non-lethal anophthalmia

Abstract

Matthew-Wood, Spear, PDAC or MCOPS9 syndrome are alternative names used to refer to combinations of microphthalmia/anophthalmia, malformative cardiac defects, pulmonary dysgenesis, and diaphragmatic hernia. Recently, mutations in STRA6, encoding a membrane receptor for vitamin A-bearing plasma retinol binding protein, have been identified in such patients. We performed STRA6 molecular analysis in three fetuses and one child diagnosed with Matthew-Wood syndrome and in three siblings where two adult living brothers are affected with combinations of clinical anophthalmia, tetralogy of Fallot, and mental retardation. Among these patients, six novel mutations were identified, bringing the current total of known STRA6 mutations to seventeen. We extensively reviewed clinical data pertaining to all twenty-one reported patients with STRA6 mutations (the seven of this report and fourteen described elsewhere) and discuss additional features that may be part of the syndrome. The clinical spectrum associated with STRA6 deficiency is even more variable than initially described.

An Alternative Retinoic Acid-responsive Stra6 Promoter Regulated in Response to Retinol Deficiency

“…Mutations in STRA6 can result in the Matthew-Wood syndrome, which consists of severe microphthalmia, pulmonary agenesis, bilateral diaphragmatic eventration, duodenal stenosis, pancreatic malformations, and growth retardation (13,20,21). Some mutations in STRA6 in humans involve either a homozygous insertion/deletion in exon 2 or a homozygous insertion in exon 7, predicting a premature stop codon (20).…”

Liver Retinol Transporter and Receptor for Serum Retinol-binding Protein (RBP4)

“…In addition, both proteins have predicted intracellular C-terminal soluble domains containing 74 -75 amino acids (Table 2). Remarkably, five of six amino acids affected by missense mutations in HMS9 (20,21) are conserved in the alignment of Stra6 with RBPR2, suggesting analogous roles for these residues in the function or structural integrity of the two proteins (Figs. 1 and 2A and Table 2).…”

“…HMS9 is a congenital complex of micro-ophthalmia, mental retardation, and severe pulmonary, diaphragmatic, gastrointestinal, and in some cases, pancreatic malformations (22,23); these specific anomalies are consistent with the established role of retinoic acid in organogenesis, embryonic patterning, and limb and nervous system development (24 -27). HMS9 results from homozygous missense or truncating mutations of Stra6 that disrupt RBP4 binding and retinol transport or destabilize the protein (21).…”

Retinal-chitosan Conjugates Effectively Deliver Active Chromophores to Retinal Photoreceptor Cells in Blind Mice and Dogs

“…With approaches in gene therapy recently approved by the FDA for LCA patients, chromophore supplementation therapy as described in his study could serve in the capacity as a combination treatment. One limitation, however, should be noted, that retinoid therapy would not be recommended for pregnant women because it may interfere with visiatin A in the developing fetus (Chassaing et al, 2009;Mahan and Vallet, 1997).…”