Human MAMLD1 Gene Variations Seem Not Sufficient to Explain a 46,XY DSD Phenotype

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Nov 19

PMID 26580071

Citations 8

Authors

Nuria Camats

Monica Fernandez-Cancio

Laura Audi

Primus E Mullis

Francisca Moreno

Isabel Gonzalez Casado

Juan Pedro Lopez-Siguero

Raquel Corripio

Jose Antonio Bermudez de la Vega

Jose Antonio Blanco

Christa E Fluck

Affiliations

Soon will be listed here.

Abstract

MAMLD1 is thought to cause disordered sex development in 46,XY patients. But its role is controversial because some MAMLD1 variants are also detected in normal individuals, several MAMLD1 mutations have wild-type activity in functional tests, and the male Mamld1-knockout mouse has normal genitalia and reproduction. Our aim was to search for MAMLD1 variations in 108 46,XY patients with disordered sex development, and to test them functionally. We detected MAMDL1 variations and compared SNP frequencies in controls and patients. We tested MAMLD1 transcriptional activity on promoters involved in sex development and assessed the effect of MAMLD1 on androgen production. MAMLD1 expression in normal steroid-producing tissues and mutant MAMLD1 protein expression were also assessed. Nine MAMLD1 mutations (7 novel) were characterized. In vitro, most MAMLD1 variants acted similarly to wild type. Only the L210X mutation showed loss of function in all tests. We detected no effect of wild-type or MAMLD1 variants on CYP17A1 enzyme activity in our cell experiments, and Western blots revealed no significant differences for MAMLD1 protein expression. MAMLD1 was expressed in human adult testes and adrenals. In conclusion, our data support the notion that MAMLD1 sequence variations may not suffice to explain the phenotype in carriers and that MAMLD1 may also have a role in adult life.

Citing Articles

A novel MAMLD1 variant in a newborn with hypospadias and elevated 17-hydroxyprogesterone.

Wang J, Sun Y, Deng Q, Wang X, Cai W, Chen Y Hormones (Athens). 2023; 23(1):171-178.

PMID: 37996649 DOI: 10.1007/s42000-023-00513-y.

A New Variant in an Infant With Microphallus and Hypospadias With Hormonal Pattern Suggesting Partial Hypogonadotropic Hypogonadism-Case Report.

Yeste D, Aguilar-Riera C, Canestrino G, Fernandez-Alvarez P, Clemente M, Camats-Tarruella N Front Endocrinol (Lausanne). 2022; 13:884107.

PMID: 35837313 PMC: 9274080. DOI: 10.3389/fendo.2022.884107.

Disorders of Sex Development in Individuals Harbouring Variants: WES and Interactome Evidence of Oligogenic Inheritance.

Li L, Gao F, Fan L, Su C, Liang X, Gong C Front Endocrinol (Lausanne). 2021; 11:582516.

PMID: 33424767 PMC: 7786837. DOI: 10.3389/fendo.2020.582516.

Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature.

Li L, Su C, Fan L, Gao F, Liang X, Gong C Orphanet J Rare Dis. 2020; 15(1):188.

PMID: 32690052 PMC: 7370409. DOI: 10.1186/s13023-020-01459-9.

Oligogenic Origin of Differences of Sex Development in Humans.

Camats N, Fluck C, Audi L Int J Mol Sci. 2020; 21(5).

PMID: 32155719 PMC: 7084473. DOI: 10.3390/ijms21051809.

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