Pigmentation-Independent Susceptibility Loci for Actinic Keratosis Highlighted by Compound Heterozygosity Analysis

Zhong, Kaiyin; Verkouteren, Joris A.C.; Jacobs, Leonie C.; Uitterlinden, André G.; Hofman, Albert; Liu, Fan; Nijsten, Tamar; Kayser, Manfred

doi:10.1016/j.jid.2016.09.007

Cited by 11 publications

(13 citation statements)

References 32 publications

(47 reference statements)

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“…Together with the Harvard cohorts we demonstrated for the first time that the genetic predisposition did not reveal new loci for developing multiple skin cancers [161], but based on clinical characteristics we developed a prognostic model [162]. In collaboration with other international consortia, the genetics of actinic keratosis, basal and squamous cell carcinoma, and melanoma have been further unraveled [163][164][165][166].…”

Section: Main Results In the Last 3 Yearsmentioning

confidence: 99%

Objectives, design and main findings until 2020 from the Rotterdam Study

et al. 2020

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The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.

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Section: Main Results In the Last 3 Yearsmentioning

confidence: 99%

Objectives, design and main findings until 2020 from the Rotterdam Study

et al. 2020

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“…TYR SNVs are also genetically associated with susceptibility to cutaneous squamous cell carcinoma (SCC) ( Asgari et al, 2016 ), the second most common cancer in the United States, and to its precursor, actinic keratosis ( Jacobs et al, 2015 ). Interestingly, this association is independent of skin color ( Jacobs et al, 2015 ; Asgari et al, 2016 ; Zhong et al, 2017 ). Over 100 TYR SNVs have been associated with disease phenotypes, while just a handful of variants are prevalent in the population at large.…”

Section: Introductionmentioning

confidence: 92%

Biophysical Compatibility of a Heterotrimeric Tyrosinase-TYRP1-TYRP2 Metalloenzyme Complex

et al. 2021

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Tyrosinase (TYR) is a copper-containing monooxygenase central to the function of melanocytes. Alterations in its expression or activity contribute to variations in skin, hair and eye color, and underlie a variety of pathogenic pigmentary phenotypes, including several forms of oculocutaneous albinism (OCA). Many of these phenotypes are linked to individual missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. We previously showed that two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Accordingly, to investigate whether TYR, TYRP1, and TYRP2 are biophysically compatible with various heterocomplexes, we computationally docked a high-quality 3D model of TYR to the crystal structure of TYRP1 and to a high-quality 3D model of TYRP2. Remarkably, the resulting TYR-TYRP1 heterodimer was complementary in structure and energy with the TYR-TYRP2 heterodimer, with TYRP1 and TYRP2 docking to different adjacent surfaces on TYR that apposed a third realistic protein interface between TYRP1-TYRP2. Hence, the 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex. In addition, this heterotrimeric TYR-TYRP1-TYRP2 positioned the C-terminus of each folded enzymatic domain in an ideal position to allow their C-terminal transmembrane helices to form a putative membrane embedded three-helix bundle. Finally, pathogenic TYR mutations causing OCA1A, which also destabilize TYR biochemically, cluster on an unoccupied protein interface at the periphery of the heterotrimeric complex, suggesting that this may be a docking site for OCA2, an anion channel. Pathogenic OCA2 mutations result in similar phenotypes to those produced by OCA1A TYR mutations. While this complex may be difficult to detect in vitro, due to the complex environment of the vertebrate cellular membranous system, our results support the existence of a heterotrimeric complex in melanogenesis.

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“…Several skin color genes such as IRF4, MC1R, ASIP and BCN2 were significantly associated with these premalignant skin lesions independently from skin color. Using compound heterozygosity analysis, several other pigment related genes were identified for AK [ 170 ].…”

Section: Dermatological Diseasesmentioning

confidence: 99%

The Rotterdam Study: 2018 update on objectives, design and main results

et al. 2017

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The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1500 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

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Pigmentation-Independent Susceptibility Loci for Actinic Keratosis Highlighted by Compound Heterozygosity Analysis

Cited by 11 publications

References 32 publications

Objectives, design and main findings until 2020 from the Rotterdam Study

Objectives, design and main findings until 2020 from the Rotterdam Study

Biophysical Compatibility of a Heterotrimeric Tyrosinase-TYRP1-TYRP2 Metalloenzyme Complex

The Rotterdam Study: 2018 update on objectives, design and main results

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