Genetic mechanisms leading to primary amenorrhea in balanced X-autosome translocations.
OBJECTIVE
To map the X-chromosome and autosome breakpoints in women with balanced X-autosome translocations and primary amenorrhea, searching candidate genomic loci for female infertility.


METHODS
Retrospective and case-control study.


METHODS
University-based research laboratory.


METHODS
Three women with balanced X-autosome translocation and primary amenorrhea.


METHODS
Conventional cytogenetic methods, genomic array, array painting, fluorescence in situ hybridization, and quantitative reverse transcription-polymerase chain reaction.


METHODS
Karyotype, copy number variation, breakpoint mapping, and gene expression levels.


RESULTS
All patients presented with breakpoints in the Xq13q21 region. In two patients, the X-chromosome breakpoint disrupted coding sequences (KIAA2022 and ZDHHC15 genes). Although both gene disruptions caused absence of transcription in peripheral blood, there is no evidence that supports the involvement of these genes with ovarian function. The ZDHHC15 gene belongs to a conserved syntenic region that encompasses the FGF16 gene, which plays a role in female germ line development. The break in the FGF16 syntenic block may have disrupted the interaction between the FGF16 promoter and its cis-regulatory element. In the third patient, although both breakpoints are intergenic, a gene that plays a role in the DAX1 pathway (FHL2 gene) flanks distally the autosome breakpoint. The FHL2 gene may be subject to position effect due to the attachment of an autosome segment in Xq21 region.


CONCLUSIONS
The etiology of primary amenorrhea in balanced X-autosome translocation patients may underlie more complex mechanisms than interruption of specific X-linked candidate genes, such as position effect. The fine mapping of the rearrangement breakpoints may be a tool for identifying genetic pathogenic mechanisms for primary amenorrhea.
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
Mariana
M
Moysés-Oliveira
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil; Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
Roberta Dos Santos
Rdos S
Guilherme
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
Anelisa Gollo
AG
Dantas
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
Renata
R
Ueta
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
Ana Beatriz
AB
Perez
Departament of Gynecology, Universidade Federal de São Paulo, São Paulo, Brazil.
Mauro
M
Haidar
Genetics Division, Hospital do Servidor Público do Estado de São Paulo, São Paulo, Brazil.
Rosane
R
Canonaco
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
Vera Ayres
VA
Meloni
Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
Nadezda
N
Kosyakova
Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
Thomas
T
Liehr
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil.
Gianna Maria
GM
Carvalheira
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil. Electronic address: melaragno.morf@epm.br.
Maria Isabel
MI
Melaragno
D000568:Amenorrhea / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D056905:Chromosome Breakpoints; D020223:Chromosome Painting; D041321:Chromosomes, Human, X; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000235:genetics; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D060850:LIM-Homeodomain Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; C512705:FGF16 protein, human; C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; C000598871:NEXMIF protein, human; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C505905:ZDHHC15 protein, human; D005346:Fibroblast Growth Factors
X-chromosome; female fertility; position effect; primary amenorrhea; reciprocal translocation