Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6.
Retinoic acid (RA) is a potent teratogen in all vertebrates when tight homeostatic controls on its endogenous dose, location, or timing are perturbed during early embryogenesis. STRA6 encodes an integral cell-membrane protein that favors RA uptake from soluble retinol-binding protein; its transcription is directly regulated by RA levels. Molecular analysis of STRA6 was undertaken in two human fetuses from consanguineous families we previously described with Matthew-Wood syndrome in a context of severe microphthalmia, pulmonary agenesis, bilateral diaphragmatic eventration, duodenal stenosis, pancreatic malformations, and intrauterine growth retardation. The fetuses had either a homozygous insertion/deletion in exon 2 or a homozygous insertion in exon 7 predicting a premature stop codon in STRA6 transcripts. Five other fetuses presenting at least one of the two major signs of clinical anophthalmia or pulmonary hypoplasia with at least one of the two associated signs of diaphragmatic closure defect or cardiopathy had no STRA6 mutations. These findings suggest a molecular basis for the prenatal manifestations of Matthew-Wood syndrome and suggest that phenotypic overlap with other associations may be due to genetic heterogeneity of elements common to the RA- and fibroblast growth factor-signaling cascades.
Golzio
Christelle
C
INSERM U781, Hopital Necker, Paris Cedex, France.
Martinovic-Bouriel
Jelena
J
Thomas
Sophie
S
Mougou-Zrelli
Soumaya
S
Grattagliano-Bessieres
Bettina
B
Bonniere
Maryse
M
Delahaye
Sophie
S
Munnich
Arnold
A
Encha-Razavi
Ferechte
F
Lyonnet
Stanislas
S
Vekemans
Michel
M
Attie-Bitach
Tania
T
Etchevers
Heather C
HC
D000015:Abnormalities, Multiple; D003241:Consanguinity; D005091:Exons; D005317:Fetal Growth Retardation / Q000235:genetics; D016368:Frameshift Mutation; D017353:Gene Deletion; D005819:Genetic Markers; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008171:Lung Diseases / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D008850:Microphthalmos / Q000235:genetics* / Q000473:pathology; D016254:Mutagenesis, Insertional; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013577:Syndrome
D005819:Genetic Markers; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; C519685:STRA6 protein, human; C027928:retinol binding protein receptor