The structure and function of the mouse tyrosinase locus

Abstract

Tyr is the mouse gene that encodes tyrosinase, an enzyme that triggers the first and rate‐limiting step in the biosynthesis of melanin. Mutations in Tyr might result in non‐functional Tyr protein and, consequently, loss of pigment production. This is a rare genetic condition, known as albinism, described for most animal species and one of the most obvious and simple phenotypes to investigate in model organisms. Mutations in the orthologous human TYR gene are associated with oculocutaneous albinism type 1 (OCA1). Over the last thirty years, the mouse Tyr locus has been studied as a paradigm for how genes and expression domains are organized and regulated in mammalian genomes. This review summarizes the major findings and experimental strategies used, from the production of conventional transgenic mice to the latest CRISPR‐Cas9 genome‐edited animals. The main conclusion inferred from all of these studies, which extends beyond the analysis of the mouse Tyr locus, is the relevance of analyzing non‐coding regulatory DNA elements in their natural chromosomal environment, and not only as randomly inserted transgenes. Further, the identification of evolutionary conserved regulatory sequences might highlight new vulnerable sites in the human TYR gene, whose mutations could also be associated with albinism.

Tyr is Responsible for the Cctq1a QTL and Links Developmental Environment to Central Corneal Thickness Determination

“…However, Tyr was a surprising gene to find linked to CCT. TYR is an oxidase whose only known biological role relates to melanin synthesis 26, 35 . Although there are small numbers of pigmented cells in the corneal limbus, the cornea is by and large not only non-pigmented, but transparent.…”

“…A leading candidate for contributing to the molecular mechanism causing thin CCT in albino mice was DOPA, which is a cofactor for TYR 26, 35 , a substrate for TH leading to dopamine (reviewed in 27 ), and an endogenous ligand for the G-protein-coupled receptor GPR143 44 . DOPA can modulate refractive development 27, 29, 40 and the circadian system 45 , as well development of multiple ocular tissues 46, 47 .…”

Genetics of non‐syndromic and syndromic oculocutaneous albinism in human and mouse

“…A recent review on this subject summarized how the mouse Tyr locus has been investigated and defined through many transgenic and CRISPR genome‐edited mouse models (Seruggia et al., 2021). Studies in mice have been instrumental to define the regulatory elements surrounding the Tyr locus and to establish their role in the overall regulation of gene expression (Giraldo et al., 2003; Seruggia et al., 2015, 2020) (Figure 1).…”

“…In addition to clinical observations, our knowledge on albinism has been greatly advanced thanks to the studies done with animal models of albinism, mainly mice. Particularly with mouse models for the most common (in Western countries) type of non‐syndromic albinism, OCA1, associated with mutations in the Tyr gene (Giraldo & Montoliu, 2002; Giraldo et al., 2003; Lavado & Montoliu, 2006; Montoliu et al., 1996; Seruggia et al., 2015, 2020, 2021). Other existing mouse models of albinism involve almost every other type of albinism (Montoliu & Marks, 2017).…”

Nobel Prize in Chemistry 2020: A Prize That Arose in Spain and Passed By

“…La segunda limitación es la fuente plejos CRISPR-Cas9 para que actúen en cis se puede fomentar la deleción de las secuencias que hay entre medio, siendo posible la eliminación específica de elementos reguladores, y el estudio de sus consecuencias en la expresión génica y el fenotipo del animal. Este tipo de estrategias ya ha sido aplicado con gran éxito en el estudio de los elementos reguladores del locus de la tirosinasa del genoma de ratón (39,40,41).…”