A patient-based medaka alg2 mutant as a model for hypo-N-glycosylation

Abstract

Defects in the evolutionarily conserved protein-glycosylation machinery during embryonic development are often fatal. Consequently, congenital disorders of glycosylation (CDG) in human are rare. We modelled a putative hypomorphic mutation described in an alpha-1,3/1,6-mannosyltransferase (ALG2) index patient (ALG2-CDG) to address the developmental consequences in the teleost medaka (Oryzias latipes). We observed specific, multisystemic, late-onset phenotypes, closely resembling the patient's syndrome, prominently in the facial skeleton and in neuronal tissue. Molecularly, we detected reduced levels of N-glycans in medaka and in the patient's fibroblasts. This hypo-N-glycosylation prominently affected protein abundance. Proteins of the basic glycosylation and glycoprotein-processing machinery were over-represented in a compensatory response, highlighting the regulatory topology of the network. Proteins of the retinal phototransduction machinery, conversely, were massively under-represented in the alg2 model. These deficiencies relate to a specific failure to maintain rod photoreceptors, resulting in retinitis pigmentosa characterized by the progressive loss of these photoreceptors. Our work has explored only the tip of the iceberg of N-glycosylation-sensitive proteins, the function of which specifically impacts on cells, tissues and organs. Taking advantage of the well-described human mutation has allowed the complex interplay of N-glycosylated proteins and their contribution to development and disease to be addressed.

Characterizing medaka visual features using a high-throughput optomotor response assay

“…The advantages of medaka as a vertebrate genetic model system include short generation time, transparent embryos, numerous offspring, a small genome size (about 700 Mb) and easy husbandry [1,2]. The full repertoire of genome editing tools is available to generate transgenic lines, gene knockout models or human disease models [3][4][5]. In addition, its high tolerance towards inbreeding enabled the establishment of the first near-isogenic vertebrate population panel [1,[6][7][8][9] to explore the genetics underlying a given phenotype [10].…”

Characterizing medaka visual features using a high-throughput optomotor response assay

“…The advantages of medaka as a vertebrate genetic model system include short generation time, transparent embryos, numerous offspring, a small genome size (about 700 Mb) and easy husbandry [ 1 , 2 ]. The full repertoire of genome editing tools is available to generate transgenic lines, gene knockout models or human disease models [ 3 – 5 ]. In addition, its high tolerance towards inbreeding enabled the establishment of the first near-isogenic vertebrate population panel [ 1 , 6 – 9 ] to explore the genetics underlying a given phenotype [ 10 ].…”