Dataset Information

Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease.

ABSTRACT: Gestational vitamin A (retinol) deficiency poses a risk for ocular birth defects and blindness. We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia. The mutant phenotypes exhibit dominant inheritance, but incomplete penetrance. Maternal transmission significantly increases the probability of phenotypic expression. RBP normally delivers retinol from hepatic stores to peripheral tissues, including the placenta and fetal eye. The disease mutations greatly reduce retinol binding to RBP, yet paradoxically increase the affinity of RBP for its cell surface receptor, STRA6. By occupying STRA6 nonproductively, the dominant-negative proteins disrupt vitamin A delivery from wild-type proteins within the fetus, but also, in the case of maternal transmission, at the placenta. These findings establish a previously uncharacterized mode of maternal inheritance, distinct from imprinting and oocyte-derived mRNA, and define a group of hereditary disorders plausibly modulated by dietary vitamin A.

SUBMITTER: Chou CM

PROVIDER: S-EPMC4409664 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease.

Chou Christopher M CM Nelson Christine C Tarlé Susan A SA Pribila Jonathan T JT Bardakjian Tanya T Woods Sean S Schneider Adele A Glaser Tom T

Cell 20150401 3

Gestational vitamin A (retinol) deficiency poses a risk for ocular birth defects and blindness. We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia. The mutant phenotypes exhibit dominant inheritance, but incomplete penetrance. Maternal transmission significantly increases the probability of phenotypic expression. RBP normally delivers retinol from hepatic stores to peri ...[more]

PMID: 25910211

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Project description:The role of the prokineticin 2 pathway in human reproduction, olfactory bulb morphogenesis, and gonadotropin-releasing hormone secretion is well established. Recent studies have highlighted the implication of di/oligogenic inheritance in this disorder. In the present study, we aimed to identify the genetic mechanisms that could explain incomplete penetrance in hypogonadotropic hypogonadism (HH). This study involved two unrelated Tunisian patients with HH, which was triggered by identifying a homozygous p.(Pro290Ser) mutation in the PROKR2 gene in a girl (HH1) with Kallmann syndrome (KS). The functional effect of this variant has previously been well demonstrated. Unexpectedly, her unaffected father (HH1P) and brother (HH1F) also carried this genetic variation at a homozygous state. In the second family, we identified a heterozygous p.(Lys205del) mutation in PROKR2, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a CCDC141 variant (c.2803C > T) was involved in 18 pathogenic digenic combinations. The CCDC141 variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between DUSP6 and SEMA7A genes, predicted as "dual molecular diagnosis." The SEMA7A variant p.(Glu436Lys) is novel and predicted as a VUS by Varsome. Sanger validation revealed the absence of this variant in the healthy mother. We hypothesize that disease expression in HH12 could be induced by the digenic transmission of the SEMA7A and DUSP6 variants or a monogenic inheritance involving only the SEMA7A VUS if further functional assays allow its reclassification into pathogenic. Our findings confirm that homozygous loss-of-function genetic variations are insufficient to cause KS, and that oligogenism is most likely the main transmission mode involved in Congenital Hypogonadotropic Hypogonadism.

Dataset Information

Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease.

Publications

Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease.

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