A Novel Hemizygous Mutation of &lt;b&gt;&lt;i&gt;MAMLD1&lt;/i&gt;&lt;/b&gt; in a Patient with 46,XY Complete Gonadal Dysgenesis

Ruiz-Arana, Inge-Lore; Hübner, Angela; Cetingdag, Cigdem; Krude, Heiko; Grüters, Annette; Fukami, Maki; Biebermann, Heike; Köhler, Birgit

doi:10.1159/000371603

Cited by 21 publications

(20 citation statements)

References 33 publications

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“…They are all located between exon 4 and intron 6 ( Fig 1B ) and show the following genotype-phenotype characteristics. Most mutations are only found in DSD patients which present with a broad range of mild to severe phenotype [c325delG (6), S143X [ 6 ], E182fsX121 [ 4 ], E197X, [ 3 ], T202M (present study), L210X and D211N (present study), Q270X, [ 3 ], H347Q [ 6 ] (present study), P384L [ 6 ], Q501Q502 (present study), A503E (present study), Q580R [ 3 ], Q602K [ 7 ], K682fsX1070 [ 9 ], 614ins3Q [ 4 ], P677L [ 10 ], L724V (present study), R726X, [ 3 ], S730S (present study), D759D [ 7 ]]. Others are carried by patients and controls [P359S [ 3 , 5 , 7 ] (present study), V505A [ 4 , 7 ] (present study), 604ins3Q [ 7 ], N662S [ 3 , 5 – 7 ] (present study)].…”

Section: Discussionmentioning

confidence: 68%

“…MAMLD1 presents with 3 different isoforms ( Fig 1A ). Isoform 2 (NM_005491.4, NP_005482, ENST00000262858, 774 amino acids), which is coded by exons 2 to 7, is considered the canonical sequence and has been studied previously [ 3 , 6 , 10 , 11 , 14 ]. Isoform 3 (NM_001177466, NP_001170937, ENST00000426613, 749 amino acids) is identical to isoform 2, but lacks exon 3.…”

Section: Resultsmentioning

confidence: 99%

“…Some patients present with cryptorchidism [ 3 , 4 , 6 ] and/or microphallus [ 6 , 7 ]. Recently, the MAMLD1 gene variation P677L was found in a 46,XY patient with complete gonadal dysgenesis [ 10 ]. In addition, two 46,XY DSD brothers with the MAMLD1 mutation Q580R presented with female external genitalia.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

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

et al. 2015

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“…60 A MAMLD1 missense mutation has also been described in a gonadal dysgenesis syndrome (p.P677L) with a severely reduced in vitro transactivation of the promoter of target gene HES3. 61 Splice site mutations are suspected to induce hypospadias with normal expression of the full-length transcript and reduced expression of a splice transcript without exon 4 62 MAMLD1 is coexpressed in fetal Leydig cells at the time of genital development with steroidogenic factor (NR5A1), and an NR5A1 target site was found within the MAMLD1 gene. 59,63,64 In Leydig cells, MAMLD1 increases the expression of CYP17A1 and permits the production of a testosterone required for male differentiation.…”

Section: Androgen Biosynthesis Defectsmentioning

confidence: 99%

Molecular genetics of hypospadias and cryptorchidism recent developments

et al. 2018

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During the last decade, a tremendous amount of work has been devoted to the study of the molecular genetics of isolated hypospadias and cryptorchidism, two minor forms of disorders of sex development (DSD). Beyond the genes involved in gonadal determination and sex differentiation, including those underlying androgen biosynthesis and signaling, new genes have been identified through genome-wide association study and familial clustering. Even if no single genetic defect can explain the whole spectrum of DSD, these recent studies reinforce the strong role of the genetic background in the occurrence of these defects. The timing of signaling disruption may explain the different phenotypes.

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“…Des mutations non-sens de ce gène sont à l'origine de 46XY DSD, et des mutations hétérozygotes sont décrites dans le cas d'hypospades isolés. Une participation de MALMD1 dans le développement ovarien n'est pas exclue (patient 46XX DSD avec virilisation et mutation gain de fonction) [19][20][21] ;…”

Section: Développement Génital Masculin (Fig 1) Détermination Testicunclassified

Le développement des organes génitaux

Kalfa¹,

Mahamat-Nour

Philibert³

et al. 2015

Rev. med. perinat.

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Reçu le 15 juin 2015 ; accepté le 2 juillet 2015 © Lavoisier SAS 2015Résumé Le système génital se développe à partir des crêtes urogénitales, et les cellules germinales primitives migrent de la vésicule vitelline dans les crêtes génitales à la sixième semaine pour former les cordons sexuels primaires. Le gène SRYest nécessaire à la formation des testicules et à la cascade de la détermination et de la différenciation sexuelle masculine. Cependant, la différenciation génitale féminine n'est probablement pas un phénomène totalement passif et fait intervenir des gènes multiples au moment de la détermina-tion gonadique. Les gènes FOXL2, WNT4 et Rspondin 1 participent à la détermination ovarienne tandis que les gènes SRY, SOX9, DAX1, DMRT1, ATRX, TSPY et MALMD1 participent à la détermination testiculaire. Le développement différentiel des canaux mésonéphrotiques et paramésoné-phrotiques permet le dimorphisme sexuel interne, celui du tubercule génital et des bourrelets génitaux permet le dimorphisme sexuel externe. Mots clés Détermination sexuelle · Différenciation sexuelle · Anomalies du développement sexuel (ADS) · GénétiqueAbstract The genital system is derived from the urogenital ridge and the primordial germ cells migrate from the posterior extremity of the embryo at 6th week to participate in the formation of the primitive sex cords. The sex-determining region Y (SRY) gene is necessary to induce the male determination and subsequent genital differentiation. The female genital development is nevertheless not a totally passive process and many genes are implicated in the development of ovary and follicles. FOXL2, WNT4, and Rspondin 1 play an important role here, whereas SRY, SOX9, DAX1, DMRT1, ATRX, TSPY, and MALMD1 are implicated in testis determination. The differential development of mesonephric and paramesonephric ducts allows the internal sexual dimorphism, while the differential development of genital tubercle and genital folds allows the external sexual dimorphism.

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A Novel Hemizygous Mutation of <b><i>MAMLD1</i></b> in a Patient with 46,XY Complete Gonadal Dysgenesis

Cited by 21 publications

References 33 publications

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

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

Molecular genetics of hypospadias and cryptorchidism recent developments

Le développement des organes génitaux

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