title: A new submicroscopic deletion that refines the 9p region for sex reversal.
abstract: Male to female sex reversal has been described in patients with deletions of chromosome 9p, and a region critical for sex reversal has been localized to p24.3, at the tip of the chromosome (TD9). It was proposed that the sex reversal may arise by haploinsufficiency for a gene localized to the minimum deletion. The 9p24.3 genes DMRT1 and DMRT2 are the favorite TD9 candidates to date, in virtue of their sequence similarity to doublesex and mab-3, sexual regulators in Drosophila and Caenorhabditis elegans, respectively. The hypothesis of sex reversal by combined haploinsufficiency for the two genes was put forward to explain the lack of mutations in either gene in XY sex-reversed females. Here we describe a XY sex-reversed patient carrying a novel 9p deletion that extends over less than 700 kb of genomic DNA. This region defines the smallest interval for sex reversal found to date. DMRT1 and DMRT2 map outside this region. Our data do not support the hypothesis of combined haploinsufficiency for DMRT1 and DMRT2. Nevertheless, DMRT1 localizes very close to the deletion breakpoint and has a pattern of expression compatible with a role in sex determination. It therefore remains a candidate gene for 9p sex reversal.
authors.affiliation: Dipartimento Patologia Umana ed Ereditaria, Università degli Studi di Pavia, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Calvari
authors.forename: V
authors.initials: V
authors.lastname: Bertini
authors.forename: A
authors.initials: A
authors.lastname: De Grandi
authors.forename: G
authors.initials: G
authors.lastname: Peverali
authors.forename: O
authors.initials: O
authors.lastname: Zuffardi
authors.forename: M
authors.initials: M
authors.lastname: Ferguson-Smith
authors.forename: J
authors.initials: J
authors.lastname: Knudtzon
authors.forename: G
authors.initials: G
authors.lastname: Camerino
authors.forename: G
authors.initials: G
authors.lastname: Borsani
authors.forename: S
authors.initials: S
authors.lastname: Guioli
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015152:Blotting, Northern; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D012734:Disorders of Sex Development; D005260:Female; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020161:Physical Chromosome Mapping; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C110547:DMRT1 protein; C119852:DMRT2 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors