Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review
Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases. Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers a...
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Veröffentlicht in: | Sexual development 2022-11, Vol.16 (2-3), p.92-97 |
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description | Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases. Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers appear to have normal fertility and no developmental abnormalities. Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified. Where studied, these variants have been modeled to alter the local MAP3K1 folding and surface domains and have been shown to alter interactions with known binding partners. The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination. |
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Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers appear to have normal fertility and no developmental abnormalities. Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified. Where studied, these variants have been modeled to alter the local MAP3K1 folding and surface domains and have been shown to alter interactions with known binding partners. The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination.</description><identifier>ISSN: 1661-5425</identifier><identifier>EISSN: 1661-5433</identifier><identifier>DOI: 10.1159/000522428</identifier><identifier>PMID: 35290982</identifier><language>eng</language><publisher>Basel, Switzerland: S. 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The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination.</description><subject>Cellular signal transduction</subject><subject>Gonadal Dysgenesis - genetics</subject><subject>Gonadal Dysgenesis, 46,XY - genetics</subject><subject>Gonadal Dysgenesis, 46,XY - pathology</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Male</subject><subject>MAP Kinase Kinase Kinase 1 - genetics</subject><subject>Review Article</subject><subject>Testis - pathology</subject><issn>1661-5425</issn><issn>1661-5433</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0c1LHDEYBvBQKmpXD95FAr204No3X_Phbdl2VVQqthU9hUzmzTY6O2OT2ar_vZFdFwTJISH8nsCbh5AdBgeMqfIbACjOJS8-kE2WZWyopBAfV2euNsinGG8BMuBcrZMNoXgJZcE3yeTC9H-7Kbbe0isTvGn7SH1Lz0cX4pTRsZlHpDLbv76hR11ratPQ708xeYw-HtIRvcT_Hh-2yJozTcTt5T4gfyY_fo-Ph2c_j07Go7OhlZL3Q1YBqznjUAoBFlUppKgqZ00l8hpzm6OzhXJlIaRRQuSVzApZq6y2UjnnlBiQL4t370P3b46x1zMfLTaNabGbR80zCSBzkJDo5wWdmga1b13XB2NfuB7lPAMBnLGkDt5RadU487Zr0fl0_ybw9U0gmR4f-2n6qKhPfl2-a23oYgzo9H3wMxOeNAP90pxeNZfs3nKyeTXDeiVfq0pgdwHuTJhiWIFl_hmdyZYL</recordid><startdate>20221101</startdate><enddate>20221101</enddate><creator>Ostrer, Harry</creator><general>S. 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subjects | Cellular signal transduction Gonadal Dysgenesis - genetics Gonadal Dysgenesis, 46,XY - genetics Gonadal Dysgenesis, 46,XY - pathology Heterozygote Humans Male MAP Kinase Kinase Kinase 1 - genetics Review Article Testis - pathology |
title | Pathogenic Variants in MAP3K1 Cause 46,XY Gonadal Dysgenesis: A Review |
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