Phenotypic spectrum of STRA6 mutations: From Matthew-Wood syndrome to non-lethal anophthalmia

INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, 31300 France.
Human Mutation (Impact Factor: 5.14). 04/2009; 30(5):E673-81. DOI: 10.1002/humu.21023
Source: PubMed


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.

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Available from: Heather Corbett Etchevers,
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    • "Pasutto et al. [6] observed that mutations in STRA6 correlated with many eye, heart, diaphragm and lung malformations as well as mental retardation in Matthew-Wood syndrome in humans, corroborating its reported roles in vitamin A uptake by cells as vitamin A is vital in organogenesis. Recent reports indicate that single nucleotide polymorphisms or mutations in STRA6 gene are correlated with the congenital eye malformations microphthalmia, anophthalmia and coloboma [7], [8] as well as Matthew-Wood syndrome [9]. Genetic null mutation of STRA6 in mice results in significant retinoid reduction in the retinal pigment epithelium and neurosensory retina, diminished visual responses and eye morphology, although the last-mentioned defect is not as serious as in patients with STRA6 mutations [10]. "
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    ABSTRACT: Our earlier study revealed that STRA6 (stimulated by retinoic acid gene 6) was up-regulated within 3 h of TCR stimulation. STRA6 is the high-affinity receptor for plasma retinol-binding protein (RBP) and mediates cellular vitamin A uptake. We generated STRA6 knockout (KO) mice to assess whether such up-regulation was critical for T-cell activation, differentiation and function. STRA6 KO mice under vitamin A sufficient conditions were fertile without apparent anomalies upon visual inspection. The size, cellularity and lymphocyte subpopulations of STRA6 KO thymus and spleen were comparable to those of their wild type (WT) controls. KO and WT T cells were similar in terms of TCR-stimulated proliferation in vitro and homeostatic expansion in vivo. Naive KO CD4 cells differentiated in vitro into Th1, Th2, Th17 as well as regulatory T cells in an analogous manner as their WT counterparts. In vivo experiments revealed that anti-viral immune responses to lymphocytic choriomeningitis virus in KO mice were comparable to those of WT controls. We also demonstrated that STRA6 KO and WT mice had similar glucose tolerance. Total vitamin A levels are dramatically lower in the eyes of KO mice as compared to those of WT mice, but the levels in other organs were not significantly affected after STRA6 deletion under vitamin A sufficient conditions, indicating that the eye is the mouse organ most sensitive to the loss of STRA6. Our results demonstrate that 1) in vitamin A sufficiency, the deletion of STRA6 in T cells does no affect the T-cell immune responses so-far tested, including those depend on STAT5 signaling; 2) STRA6-independent vitamin A uptake compensated the lack of STRA6 in lymphoid organs under vitamin A sufficient conditions in mice; 3) STRA6 is critical for vitamin A uptake in the eyes even in vitamin A sufficiency.
    PLoS ONE 12/2013; 8(12):e82808. DOI:10.1371/journal.pone.0082808 · 3.23 Impact Factor
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    • "Currently, 17 different STRA6 mutations (eight missense, three nonsense, and six frameshift) have been found in patients with MWS [Chassaing et al., 2009]. The clinical spectrum associated with STRA6 mutations is extremely variable and no correlations between the nature of a STRA6 mutation and phenotypic severity have been found [Chassaing et al., 2009]. The current study has shown that patients homozygous for the STRA6 p.G304K mutation can develop an isolated eye phenotype (pedigrees 1 and 2) or the more severe MWS (pedigree 3), raising the question of how the G304K mutation produces an isolated eye malformation of variable severity in some patients but a multisystem disorder in others? "
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    ABSTRACT: Microphthalmia, anophthalmia, and coloboma (MAC) are structural congenital eye malformations that cause a significant proportion of childhood visual impairments. Several disease genes have been identified but do not account for all MAC cases, suggesting that additional risk loci exist. We used single nucleotide polymorphism (SNP) homozygosity mapping (HM) and targeted next-generation sequencing to identify the causative mutation for autosomal recessive isolated colobomatous microanophthalmia (MCOPCB) in a consanguineous Irish Traveller family. We identified a double-nucleotide polymorphism (g.1157G>A and g.1156G>A; p.G304K) in STRA6 that was homozygous in all of the MCOPCB patients. The STRA6 p.G304K mutation was subsequently detected in additional MCOPCB patients, including one individual with Matthew-Wood syndrome (MWS; MCOPS9). STRA6 encodes a transmembrane receptor involved in vitamin A uptake, a process essential to eye development and growth. We have shown that the G304K mutant STRA6 protein is mislocalized and has severely reduced vitamin A uptake activity. Furthermore, we reproduced the MCOPCB phenotype in a zebrafish disease model by inhibiting retinoic acid (RA) synthesis, suggesting that diminished RA levels account for the eye malformations in STRA6 p.G304K patients. The current study demonstrates that STRA6 mutations can cause isolated eye malformations in addition to the congenital anomalies observed in MWS.
    Human Mutation 12/2011; 32(12):1417-26. DOI:10.1002/humu.21590 · 5.14 Impact Factor
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    • "Several recessive alleles have also been reported. Homozygous and/or compound heterozygous mutations have been identified: in Forkhead Box E3 (FOXE3) in several families affected with nonsyndromic microphthalmia, often accompanied by aphakia and anterior segment anomalies [15-19]; in Retina and Anterior Neural Fold Homeobox Gene (RAX) in two probands with nonsyndromic anophthalmia [20,21]; and in Stimulated by Retinoic Acid 6 (STRA6) in syndromic A/M patients [22-24]. "
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    ABSTRACT: To further explore the spectrum of mutations in the Visual System Homeobox 2 (VSX2/CHX10) gene previously found to be associated with autosomal recessive microphthalmia. We screened 95 probands with syndromic or isolated developmental ocular conditions (including 55 with anophthalmia/microphthalmia) for mutations in VSX2. Homozygous mutations in VSX2 were identified in two out of five consanguineous families with isolated microphthalmia. A novel missense mutation, c.668G>C (p.G223A), was identified in a large Pakistani family with multiple sibships affected with bilateral microphthalmia. This p.G223A mutation affects the conserved CVC motif that was shown to be important for DNA binding and repression activities of VSX2. The second mutation, c.249delG (p.Leu84SerfsX57), was identified in an Iranian family with microphthalmia; this mutation has been previously reported and is predicted to generate a severely truncated mutant protein completely lacking the VSX2 homeodomain, CVC domain and COOH-terminal regions. Mutations in VSX2 represent an important cause of autosomal recessive microphthalmia in consanguineous pedigrees. Identification of a second missense mutation in the CVC motif emphasizes the importance of this region for normal VSX2 function.
    Molecular vision 09/2011; 17:2527-32. · 1.99 Impact Factor
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