Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 131390 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2014

History: This disorder was first reported by Murgiano et al. (2014)

Inheritance: Murgiano et al. (2014) provided pedigree evidence for autosomal recessive inheritance.

Mapping: Murgiano et al. (2014) genotyped 4 affected half-sib calves, their 4 dams and their sire with the Illumina BovineHD BeadChip, and gathered comparable SNP genotype data from 51 other Romagnolas. A GWAS with 549,341 informative SNPs mapped the disorder to a "single contiguous genomic region (3.32–10.05 Mb) on bovine chromosome 28 (BTA 28)" which was confirmed by homozygosity mapping.

Molecular basis: As reported by Murgiano et al. (2014), the candidate region (mentioned in the Mapping section above) contains 42 annotated and several uncharacterised genes, none of which are obvious functional candidate genes for this disorder. Analysis of whole-genome sequencing data from of one of the affected calves (~x13.5) and 44 other cattle from 15 breeds narrowed the field of positional candidate causal mutations down to one SNV in an uncharacterised gene and "an 855 bp deletion across the exon 19/intron 19 border of the bovine nidogen 1 (NID1) gene (c.3579_3604+829del)". Genotyping of a larger cohort confirmed the deletion as being causal. Murgiano et al. (2014) also reported that "RT-PCR showed that NID1 is expressed in bovine lenses while the transcript of the second locus was absent. The NID1 deletion leads to the skipping of exon 19 during transcription and is therefore predicted to cause a frameshift and premature stop codon (p.1164fs27X). The truncated protein lacks a C-terminal domain essential for binding with matrix assembly complexes."

Clinical features: As described by Murgiano et al. (2014), "One calf was admitted to the teaching hospital of the Department of Veterinary Medical Sciences of the University of Bologna for in-depth clinical study. A thorough ophthalmologic examination was carried out in a darkened environment. The exam did not show any lid or and conjunctival problems, the menace was bilaterally positive, and the Shirmer tear tests as well as the intraocular pressure (IOP) values were normal. By direct focal light source stimulation, the direct and consensual pupillary reflexes were normal or slightly more accentuated. Direct ophthalomoscopy revealed a regular morphology and arrangement of the iris and net margins of the pupillary lumen. After mydriasis induction, examination of both lenses revealed mild central nuclear opacity irregularly extending towards the periphery. Partial fundus evaluation revealed a regular papilla and a normal tapetum. Hematological parameters and clinical biochemistry did not show notable alterations. The final diagnosis for this calf was bilateral incomplete immature nuclear cataract."

Breed: Romagnola (Cattle) (VBO_0000360).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: