Whole genome sequencing identifies a missense polymorphism in PADI6 associated with testicular/ovotesticular XX disorder of sex development in dogs

Nowacka‐Woszuk, Joanna; Stachowiak, Monika; Szczerbal, Izabela; Szydłowski, M.; Szabelska‐Berȩsewicz, Alicja; Zyprych-Walczak, Joanna; Krzemińska, Paulina; Nowak, Tomasz; Łukomska, Anna; Ligocka, Zuzanna; Bieżyński, Janusz; Dzimira, S.; Niżański, Wojciech; Świtoński, M.

doi:10.1016/j.ygeno.2022.110389

Cited by 3 publications

(10 citation statements)

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“…We previously detected over 14 million (14 435 602) small variants, including SNPs, indels and other non‐structural variants, on all 38 autosomes and chromosome X in 16 French Bulldogs and nine American Staffordshire Terriers (Nowacka‐Woszuk et al, 2022). To find pathogenic variations in French Bulldog, I excluded all positions that were not within any of the 26 determined identical‐by‐descent segments; over 340 000 remaining positions were included.…”

Section: Resultsmentioning

confidence: 99%

“…In this report, I reanalyze the data first presented in the paper of Nowacka‐Woszuk et al (2022) in order to search for possible harmful variants for XX DSDs in French Bulldogs and American Staffordshire Terriers. Important assumptions of this reanalysis are that XX DSD in an individual is caused by a highly penetrant recessive variant, and that there may be different recessive mutations in the two breeds and across dogs within each breed.…”

Section: Introductionmentioning

confidence: 99%

“…Quite common forms of DSD in canine populations include testicular and ovotesticular XX DSDs with a normal set of sex chromosomes (78,XX) and a lack of the Y‐linked SRY gene. XX DSDs have been studied in a reference family of American Cocker Spaniels (Meyers‐Wallen & Patterson, 1988) and, more recently, in sporadic cases of French Bulldogs and American Staffordshire Terriers (Nowacka‐Woszuk et al, 2022). Nowacka‐Woszuk et al (2022) recently presented the current state of knowledge regarding canine XX DSDs and also proposed the PADI6 gene as a promising marker associated with DSDs in dog.…”

Section: Introductionmentioning

confidence: 99%

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A clue to the etiology of disorders of sex development from identity‐by‐descent analysis in dogs with cryptic relatedness

Szydłowski

2022

Animal Genetics

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Disorders of sex development (DSDs) are discrepancies between sex chromosomes and phenotypical sex. Quite common forms of DSD in canine populations include testicular and ovotesticular XX DSDs with a normal set of sex chromosomes. The objective of this study was to identify genes and putative harmful variants for canine XX DSDs. I have reanalyzed data from the whole‐genome sequencing of 11 XX DSD French Bulldogs and six XX DSD American Staffordshire Terriers. Identity‐by‐descent analysis revealed cryptic relatedness in affected French Bulldogs. Causative genes were sought in chromosomal segments shared identical‐by‐descent by close relatives. In French Bulldogs, the reanalysis identified 19 regions of importance with a total length of just 65.9 Mb. Variant filtering within the regions implicated AKAP2, PIWIL1, POLR3A and SH2D4B as genes that may be involved in individual cases of testicular and ovotesticular XX DSD in French Bulldogs and American Staffordshire Terriers.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A clue to the etiology of disorders of sex development from identity‐by‐descent analysis in dogs with cryptic relatedness

Szydłowski

2022

Animal Genetics

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“…However, the abnormal expression of PADI family members can trigger reproductive development-related diseases. First, polymorphisms in PADI6 are associated with sexual developmental disorders ( 189 ). Second, PADI6 is one of the genes encoding the subcortical maternal complex (SCMC), which is necessary for oocyte maturation and early embryonic development.…”

Section: The Padi Family and Reproductive Development-related Diseasesmentioning

confidence: 99%

Role of the PADI family in inflammatory autoimmune diseases and cancers: A systematic review

2023

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The peptidyl arginine deiminase (PADI) family is a calcium ion-dependent group of isozymes with sequence similarity that catalyze the citrullination of proteins. Histones can serve as the target substrate of PADI family isozymes, and therefore, the PADI family is involved in NETosis and the secretion of inflammatory cytokines. Thus, the PADI family is associated with the development of inflammatory autoimmune diseases and cancer, reproductive development, and other related diseases. In this review, we systematically discuss the role of the PADI family in the pathogenesis of various diseases based on studies from the past decade to provide a reference for future research.

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“…Until now, the causative mutation affecting the expression of the FOXL2 gene involved in ovarian development has been identified only in goats [ 5 , 6 ]. In pigs, the XX DSD is associated with DNA variants in a region harboring the SOX9 gene, which plays a crucial role in development of the testes [ 7 , 8 ]; in dogs, it is associated with variants near SOX9 or PADI6 [ 9 , 10 , 11 , 12 ]. Upstream DNA variants of SOX9 are also known to cause of XX DSD in humans [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

XX/XY Chimerism in Internal Genitalia of a Virilized Heifer

Szczerbal

Nowacka‐Woszuk

Stachowiak

et al. 2022

Animals

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Five DSD heifers underwent genetic analysis in the present study. We cytogenetically analyzed in vitro cultured leukocytes and searched for SRY, AMELX/AMELY and ZFX/ZFY genes in leukocytes and hair follicles, finding that four of the studied heifers were freemartins (XX/XY leukocyte chimerism). The fifth case had an underdeveloped vulva localized ventrally and cranially to the mammary gland, a normal female sex chromosome complement (60,XX) in the leukocytes, and a lack of Y-chromosome-derived genes in the leukocytes and hair follicles. Postmortem anatomical examination of this heifer revealed the presence of normal ovaries with follicles, uterus, and oviducts, but molecular detection of the SRY, ZFX, ZFY,AMELX, and AMELY genes in these organs indicated the presence of a cell line carrying the Y chromosome. Further analysis of twelve microsatellite markers revealed the presence of additional variants at six loci in DNA samples derived from the reproductive organs; XX/XY chimerism was thus suspected in these samples. On the basis of the detection of AMELY (Y-linked) versus AMELX (X-linked) and SOX9 (autosomal) versus AMELY genes by droplet digital PCR (ddPCR), the Y/X and Y/autosome ratios were evaluated; they indicated the presence of XX and XY cell lines in the reproductive tissues. Our study showed that XX/XY chimerism can be present in the internal reproductive organs of the virilized heifers with a normal female set of sex chromosomes (60,XX) and a lack of Y-chromosome-derived genes in the leukocytes. The etiology of this phenomenon remains unknown.

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Whole genome sequencing identifies a missense polymorphism in PADI6 associated with testicular/ovotesticular XX disorder of sex development in dogs

Cited by 3 publications

References 57 publications

A clue to the etiology of disorders of sex development from identity‐by‐descent analysis in dogs with cryptic relatedness

A clue to the etiology of disorders of sex development from identity‐by‐descent analysis in dogs with cryptic relatedness

Role of the PADI family in inflammatory autoimmune diseases and cancers: A systematic review

XX/XY Chimerism in Internal Genitalia of a Virilized Heifer

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