Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 616428 (trait) , 180250 (gene) , 615147 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0014635: microphthalmia, isolated, with coloboma 10

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2018

Species-specific name: Microphthalmos

Species-specific symbol: MOD-RBP4 (Mowat et al., 2024)

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 (Dog) (VBO_0200703).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: