title: Screening of MAMLD1 mutations in 70 children with 46,XY DSD: identification and functional analysis of two new mutations.
abstract: More than 50% of children with severe 46,XY disorders of sex development (DSD) do not have a definitive etiological diagnosis. Besides gonadal dysgenesis, defects in androgen biosynthesis, and abnormalities in androgen sensitivity, the Mastermind-like domain containing 1 (MAMLD1) gene, which was identified as critical for the development of male genitalia, may be implicated. The present study investigated whether MAMLD1 is implicated in cases of severe 46,XY DSD and whether routine sequencing of MAMLD1 should be performed in these patients.Seventy children with severe non-syndromic 46,XY DSD of unknown etiology were studied. One hundred and fifty healthy individuals were included as controls. Direct sequencing of the MAMLD1, AR, SRD5A2 and NR5A1 genes was performed. The transactivation function of the variant MAMLD1 proteins was quantified by the luciferase method.TWO NEW MUTATIONS WERE IDENTIFIED: p.S143X (c.428C>A) in a patient with scrotal hypospadias with microphallus and p.P384L (c.1151C>T) in a patient with penile hypospadias with microphallus. The in vitro functional study confirmed no residual transactivating function of the p.S143X mutant and a significantly reduced transactivation function of the p.P384L protein (p = 0.0032). The p.P359S, p.N662S and p.H347Q variants are also reported with particularly high frequency of the p.359T- p.662G haplotype in the DSD patients.Severe undervirilization in XY newborns can reveal mutations of MAMLD1. MAMLD1 should be routinely sequenced in these patients with otherwise normal AR, SRD5A2 and NR5A1genes.
authors.affiliation: Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et UM1, Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kalfa
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.forename: Pascal
authors.initials: P
authors.lastname: Philibert
authors.forename: Francoise
authors.initials: F
authors.lastname: Audran
authors.forename: Catherine
authors.initials: C
authors.lastname: Pienkowski
authors.forename: Jacques
authors.initials: J
authors.lastname: Weill
authors.forename: Graziella
authors.initials: G
authors.lastname: Pinto
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.forename: Totsumo
authors.initials: T
authors.lastname: Ogata
authors.forename: Charles
authors.initials: C
authors.lastname: Sultan
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D001483:Base Sequence; D002648:Child; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D058490:Disorder of Sex Development, 46,XY / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000235:genetics; D017422:Sequence Analysis, DNA; D054339:Steroidogenic Factor 1 / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; C528016:MAMLD1 protein, human; D008565:Membrane Proteins; D050505:Mutant Proteins; C515057:NR5A1 protein, human; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human