Genetic mechanisms leading to primary amenorrhea in balanced X-autosome translocations

Moysés-Oliveira, Mariana; Guilherme, Roberta dos Santos; Dantas, Anelisa Gollo; Ueta, Renata; Perez, Ana Beatriz Alvarez; Haidar, Mauro Abi; Canonaco, Rosane S.; Meloni, Vera Ayres; Kosyakova, Nadezda; Liehr, Thomas; Carvalheira, Gianna; Melaragno, Maria Isabel

doi:10.1016/j.fertnstert.2015.01.030

Cited by 26 publications

(21 citation statements)

References 38 publications

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“…Genomic array was performed using the Affymetrix Genome‐Wide Human SNP‐Array 6.0 or Human Genome comparative genome hybridization (CGH) array 4 × 44k (Agilent Technologies, Santa Clara, MA, USA). For patient 1, breakpoint localization was performed by fluorescence in situ hybridization (FISH) and array painting as described (Liehr, Heller, Starke, & Claussen, ; Moyses‐Oliveira et al., ) and validated by FISH using bacterial artificial chromosome probe CTD‐3066N24 (Thermo Fisher Scientific, Waltham, MA, USA) and whole‐genome sequencing. X‐chromosome inactivation was assessed as described (Sisdelli et al., ).…”

Section: Methodsmentioning

confidence: 99%

Inactivation of AMMECR1 is associated with growth, bone, and heart alterations

et al. 2017

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We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis.

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Section: Methodsmentioning

confidence: 99%

Inactivation of AMMECR1 is associated with growth, bone, and heart alterations

et al. 2017

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“…We studied four women with balanced X‐autosome translocation who originally presented to genetic or endocrinological public services in São Paulo state, Brazil. Two patients (patient 2 and 4) presented with primary amenorrhea and their endocrinological and gynecological evaluation was presented elsewhere [Moyses‐Oliveira et al, ].…”

Section: Methodsmentioning

confidence: 99%

“…The dissected and DOP‐PCR amplified derivative chromosomes' DNA from the same patient—der(X) and der(A)—were labeled; one of them with Cy3 and the other with Cy5, and hybridized to the same CGH array SurePrint G3 (Agilent Technologies, Palo Alto, CA) as previously described [Moyses‐Oliveira et al, ]. Two different slide designs were used: SurePrint G3 Custom CGH 8 × 60 k designed with 46,928 probes exclusive for the X‐chromosome breakpoint definition, and SurePrint G3 Unrestricted 1 × 1M standard manufacturer design from catalog (AMADID 021529) that covers the entire genome, for the autosome breakpoint definition.…”

Section: Methodsmentioning

confidence: 99%

X‐linked intellectual disability related genes disrupted by balanced X‐autosome translocations

Moysés-Oliveira

Guilherme

Meloni

et al. 2015

American J of Med Genetics Pt B

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Detailed molecular characterization of chromosomal rearrangements involving X-chromosome has been a key strategy in identifying X-linked intellectual disability-causing genes. We fine-mapped the breakpoints in four women with balanced X-autosome translocations and variable phenotypes, in order to investigate the corresponding genetic contribution to intellectual disability. We addressed the impact of the gene interruptions in transcription and discussed the consequences of their functional impairment in neurodevelopment. Three patients presented with cognitive impairment, reinforcing the association between the disrupted genes (TSPAN7-MRX58, KIAA2022-MRX98, and IL1RAPL1-MRX21/34) and intellectual disability. While gene expression analysis showed absence of TSPAN7 and KIAA2022 expression in the patients, the unexpected expression of IL1RAPL1 suggested a fusion transcript ZNF611-IL1RAPL1 under the control of the ZNF611 promoter, gene disrupted at the autosomal breakpoint. The X-chromosomal breakpoint definition in the fourth patient, a woman with normal intellectual abilities, revealed disruption of the ZDHHC15 gene (MRX91). The expression assays did not detect ZDHHC15 gene expression in the patient, thus questioning its involvement in intellectual disability. Revealing the disruption of an X-linked intellectual disability-related gene in patients with balanced X-autosome translocation is a useful tool for a better characterization of critical genes in neurodevelopment. © 2015 Wiley Periodicals, Inc.

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“…Patient carriers of X-chromosome alteration karyotypes and HUMARA results a Karyotype described byMoysés-Oliveira et al (2015a) …”

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Incorporation of 5-ethynyl-2′-deoxyuridine (EdU) as a novel strategy for identification of the skewed X inactivation pattern in balanced and unbalanced X-rearrangements

et al. 2015

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X-chromosome inactivation occurs randomly in normal female cells. However, the inactivation can be skewed in patients with alterations in X-chromosome. In balanced X-autosome translocations, normal X is preferentially inactivated, while in unbalanced X alterations, the aberrant X is usually inactivated. Here, we present a novel strategy to verify the skewed X inactivation pattern through the incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into cells, in 11 patients: five carriers of balanced X-autosome translocations and six of unbalanced X-chromosome alterations. Since EdU is a labeled nucleoside analog of thymidine, its incorporation during DNA synthesis can reveal late replication regions and the inactive X-chromosome. All EdU findings were validated by the human androgen receptor gene (HUMARA) assay. The late replication regions were easily and quickly visualized in all cells, where inactive Xs are marked with strong green fluorescence. It was observed that the normal X-chromosome was preferentially inactivated in patients with balanced X-autosome translocations; while the aberrant X-chromosome was inactivated in most cells from patients with unbalanced alterations. By performing the fluorescence-based EdU assay, the differences between the active and inactive X-chromosomes are more easily recognizable than by classic cytogenetic methods. Furthermore, EdU incorporation allows the observation of the late replication regions in autosomal segments present in X derivatives from X-autosome translocations. Therefore, EdU assay permits an accurate and efficient cytogenetic evaluation of the X inactivation pattern with a low-cost, easy to perform and highly reproducible technique.

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Genetic mechanisms leading to primary amenorrhea in balanced X-autosome translocations

Cited by 26 publications

References 38 publications

Inactivation of AMMECR1 is associated with growth, bone, and heart alterations

Inactivation of AMMECR1 is associated with growth, bone, and heart alterations

X‐linked intellectual disability related genes disrupted by balanced X‐autosome translocations

Incorporation of 5-ethynyl-2′-deoxyuridine (EdU) as a novel strategy for identification of the skewed X inactivation pattern in balanced and unbalanced X-rearrangements

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