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OMIA:002151-9615 : Microphthalmia, isolated, with coloboma in Canis lupus familiaris

Categories: Vision / eye phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 616428 (trait) , 180250 (gene) , 615147 (trait)

Links to MONDO diseases:

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2018

Inheritance: Kaukonen et al. (2018): "The four affected litters are related in a single pedigree, with a transmission pattern suggesting an autosomal recessive mode of inheritance" (Kaukonen et al., 2018). However, the disease "manifests only if both the dam and the offspring carry homozygous mutation", i.e. this is a "Recessive RBP4 defect with maternal transmission" (Kaukonen et al., 2018)

Mapping: Via a "a genome-wide association study (GWAS) with 12 cases, 17 controls, and 172,963 SNP markers", Kaukonen et al. (2018) mapped the disorder to "a 15.7-Mb critical region on canine chromosome 28 (praw = 8.04 x 10^-9, pgenome = 1.00 x 10^-5), spanning nucleotides 287,714 to 16,036,936 bp (CanFam 3.1)"

Molecular basis: Comparison of the whole-genome sequence of one affected dog with the canine reference assembly in the candidate region eventually revealed the likely causal variant as "a 3-bp deletion (c.282_284del) in the gene encoding RBP4 gene, resulting in the loss of a single lysine (AAG codon) near the RBP amino terminus (p.K30del), in a charged segment preceding the lipocalin b-barrel domain (Figure 3). This is the 12th amino acid in the mature protein (K12del), after cleavage of the signal peptide, and it is highly conserved among vertebrates." (Kaukonen et al., 2018) "The maternal penetrance effect arises from an impairment in the sequential transfer of retinol across the placenta, via RBP encoded by maternal and fetal genomes. Our results demonstrate a mode of recessive maternal inheritance, with a physiological basis, and they extend previous observations on dominant-negative RBP4 alleles in humans [see MIM link above]." (Kaukonen et al., 2018)

Breed: Irish soft-coated wheaten terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
RBP4 retinol binding protein 4, plasma Canis lupus familiaris 28 NC_051832.1 (8090965..8083216) RBP4 Homologene, Ensembl , NCBI gene

Variants

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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
993 Irish soft-coated wheaten terrier Microphthalmia, isolated, with coloboma RBP4 deletion, small (<=20) Naturally occurring variant CanFam3.1 28 g.7830265_7830267del c.90_92del p.(K31del) XM_534969.6; XP_534969.3; published as c.282_284delGAA and p.(K30del); coordinates in the table have been updated to a recent reference genome and transcript, and are in accordance with the HGVS 3'-rule 2018 29847795
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Reference

2018 Kaukonen, M., Woods, S., Ahonen, S., Lemberg, S., Hellman, M., Hytönen, M.K., Permi, P., Glaser, T., Lohi, H. :
Maternal inheritance of a recessive RBP4 defect in canine congenital eye disease. Cell Rep 23:2643-2652, 2018. Pubmed reference: 29847795 . DOI: 10.1016/j.celrep.2018.04.118.

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  • Created by Frank Nicholas on 13 Jun 2018
  • Changed by Frank Nicholas on 13 Jun 2018