Categories: Vision / eye phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 180100 (trait) , 603937 (gene)

Links to MONDO diseases:

• MONDO:0008377: retinitis pigmentosa 1

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2016

History: In a landmark project, Michot et al. (2016) analysed the genomic sequence of 1147 bulls (representing 15 European breeds) from the 1000 bull genome project, yielding "2489 putative deleterious variants (stop lost and gained, frameshift, splice acceptor and donor sites, initiator codon variants and missense variants predicted as deleterious with a score of 0 by SIFT) that segregated at a frequency of 5 % or more in at least one of the 15 breeds represented by at least 20 genomes in run 4 of the 1000 bull genomes project". As a proof-of-principle illustration of the nature of these variants, Michot et al. (2016) "investigated the phenotypic consequences of a frameshift variant [see Molecular basis] in the retinitis pigmentosa-1 gene segregating in several breeds and at a high frequency (27 %) in Normande cattle . . . [that] causes progressive degeneration of photoreceptors leading to complete blindness in homozygotes"

Molecular basis: Michot et al. (2016): "a one base pair insertion (Chr14: g.23995411_23995412insA) that affects the retinitis pigmentosa-1 gene (RP1) . . . [and] is predicted to cause a frameshift at codon 791 and to terminate the protein 13 amino acids later (p. R791KfsX13)".

Clinical features: Michot et al. (2016): "Among the four homozygous mutant animals, two heifers aged less than 3 years had normal vision and ocular tests. In contrast, two older animals aged 4.5 and 5.5 years presented respectively marked visual deficit and blindness, in spite of normal pupillary light reflexes. Their ocular fundi showed typical features of bilateral retinal degeneration with a heterogeneous color, multiple focal areas of hyper reflectivity in the tapetal area which could be coalescent, and a reduction in the caliber of retinal blood vessels"

Pathology: Michot et al. (2016): "histological analyses revealed a total absence of photoreceptor outer segments along with a marked thinning and disorganization of the outer nuclear layer with very few remaining nuclei"

Prevalence: Michot et al. (2016): "Interestingly, 89 % (2216/2489) of these polymorphisms were observed in more than one breed and as much as 12 % (308/2489) in all 15 breeds, which indicates (subject to any unregistered crossbreeding event) that the majority of the retained variants existed prior to the splitting of the different cattle populations studied (i.e. at least 500 years ago"

Breed: Normande (Cattle) (VBO_0000322).

Associated gene: