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A missense mutation in solute carrier family 12, member 1 ( SLC12A1 ) causes hydrallantois in Japanese Black cattle

View Article: PubMed Central - PubMed

ABSTRACT

Background: Hydrallantois is the excessive accumulation of fluid within the allantoic cavity in pregnant animals and is associated with fetal mortality. Although the incidence of hydrallantois is very low in artificial insemination breeding programs in cattle, recently 38 cows with the phenotypic appearance of hydrallantois were reported in a local subpopulation of Japanese Black cattle. Of these, 33 were traced back to the same sire; however, both their parents were reported healthy, suggesting that hydrallantois is a recessive inherited disorder. To identify autozygous chromosome segments shared by individuals with hydrallantois and the causative mutation in Japanese Black cattle, we performed autozygosity mapping using single-nucleotide polymorphism (SNP) array and exome sequencing.

Results: Shared haplotypes of the affected fetuses spanned 3.52 Mb on bovine chromosome 10. Exome sequencing identified a SNP (g.62382825G > A, p.Pro372Leu) in exon 10 of solute carrier family 12, member 1 (SLC12A1), the genotype of which was compatible with recessive inheritance. SLC12A1 serves as a reabsorption molecule of Na+-K+-2Cl− in the apical membrane of the thick ascending limb of the loop of Henle in the kidney. We observed that the concentration of Na+-Cl− increased in allantoic fluid of homozygous SLC12A1 (g.62382825G > A) in a hydrallantois individual. In addition, SLC12A1-positive signals were localized at the apical membrane in the kidneys of unaffected fetuses, whereas they were absent from the apical membrane in the kidneys of affected fetuses. These results suggested that p.Pro372Leu affects the membrane localization of SLC12A1, and in turn, may impair its transporter activity. Surveillance of the risk-allele frequency revealed that the carriers were restricted to the local subpopulation of Japanese Black cattle. Moreover, we identified a founder individual that carried the mutation (g.62382825G > A).

Conclusions: In this study, we mapped the shared haplotypes of affected fetuses using autozygosity mapping and identified a de novo mutation in the SLC12A1 gene that was associated with hydrallantois in Japanese Black cattle. In kidneys of hydrallantois-affected fetuses, the mutation in SLC12A1 impaired the apical membrane localization of SLC12A1 and reabsorption of Na+-K+-2Cl− in the thick ascending limb of the loop of Henle, leading to a defect in the concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibited polyuria that accumulated in the allantoic cavity. Surveillance of the risk-allele frequency indicated that carriers were not widespread throughout the Japanese Black cattle population. Moreover, we identified the founder individual, and thus could effectively manage the disorder in the population.

Electronic supplementary material: The online version of this article (doi:10.1186/s12864-016-3035-1) contains supplementary material, which is available to authorized users.

No MeSH data available.


Pedigree analysis of hydrallantois-affected fetuses in Japanese Black cattle. Family tree showing nine hydrallantois-affected fetuses traced back two to four generations on both paternal and maternal sides to an ancestor; sire_X (magenta-filled square). Males are represented by squares, and females by circles. Affected individuals are indicated with black-filled symbols
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Fig2: Pedigree analysis of hydrallantois-affected fetuses in Japanese Black cattle. Family tree showing nine hydrallantois-affected fetuses traced back two to four generations on both paternal and maternal sides to an ancestor; sire_X (magenta-filled square). Males are represented by squares, and females by circles. Affected individuals are indicated with black-filled symbols

Mentions: Examination of the pedigree of the nine cattle suggested a recessive mode of inheritance as all the affected individuals could be traced back for two to four generations on both paternal and maternal sides to a common ancestor, sire_X (magenta-filled squares in Fig. 2). We performed PCR using a primer specific for the Y chromosome to determine the sex of the affected fetuses (Additional file 1: Table S1). Results showed that the sex ratio of males to females was 5:4 (Fig. 2, Additional file 2); there was, therefore, no sex bias in the affected fetuses, suggesting that hydrallantois is an autosomal recessive inherited disorder.Fig. 2


A missense mutation in solute carrier family 12, member 1 ( SLC12A1 ) causes hydrallantois in Japanese Black cattle
Pedigree analysis of hydrallantois-affected fetuses in Japanese Black cattle. Family tree showing nine hydrallantois-affected fetuses traced back two to four generations on both paternal and maternal sides to an ancestor; sire_X (magenta-filled square). Males are represented by squares, and females by circles. Affected individuals are indicated with black-filled symbols
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5016959&req=5

Fig2: Pedigree analysis of hydrallantois-affected fetuses in Japanese Black cattle. Family tree showing nine hydrallantois-affected fetuses traced back two to four generations on both paternal and maternal sides to an ancestor; sire_X (magenta-filled square). Males are represented by squares, and females by circles. Affected individuals are indicated with black-filled symbols
Mentions: Examination of the pedigree of the nine cattle suggested a recessive mode of inheritance as all the affected individuals could be traced back for two to four generations on both paternal and maternal sides to a common ancestor, sire_X (magenta-filled squares in Fig. 2). We performed PCR using a primer specific for the Y chromosome to determine the sex of the affected fetuses (Additional file 1: Table S1). Results showed that the sex ratio of males to females was 5:4 (Fig. 2, Additional file 2); there was, therefore, no sex bias in the affected fetuses, suggesting that hydrallantois is an autosomal recessive inherited disorder.Fig. 2

View Article: PubMed Central - PubMed

ABSTRACT

Background: Hydrallantois is the excessive accumulation of fluid within the allantoic cavity in pregnant animals and is associated with fetal mortality. Although the incidence of hydrallantois is very low in artificial insemination breeding programs in cattle, recently 38 cows with the phenotypic appearance of hydrallantois were reported in a local subpopulation of Japanese Black cattle. Of these, 33 were traced back to the same sire; however, both their parents were reported healthy, suggesting that hydrallantois is a recessive inherited disorder. To identify autozygous chromosome segments shared by individuals with hydrallantois and the causative mutation in Japanese Black cattle, we performed autozygosity mapping using single-nucleotide polymorphism (SNP) array and exome sequencing.

Results: Shared haplotypes of the affected fetuses spanned 3.52 Mb on bovine chromosome 10. Exome sequencing identified a SNP (g.62382825G > A, p.Pro372Leu) in exon 10 of solute carrier family 12, member 1 (SLC12A1), the genotype of which was compatible with recessive inheritance. SLC12A1 serves as a reabsorption molecule of Na+-K+-2Cl− in the apical membrane of the thick ascending limb of the loop of Henle in the kidney. We observed that the concentration of Na+-Cl− increased in allantoic fluid of homozygous SLC12A1 (g.62382825G > A) in a hydrallantois individual. In addition, SLC12A1-positive signals were localized at the apical membrane in the kidneys of unaffected fetuses, whereas they were absent from the apical membrane in the kidneys of affected fetuses. These results suggested that p.Pro372Leu affects the membrane localization of SLC12A1, and in turn, may impair its transporter activity. Surveillance of the risk-allele frequency revealed that the carriers were restricted to the local subpopulation of Japanese Black cattle. Moreover, we identified a founder individual that carried the mutation (g.62382825G > A).

Conclusions: In this study, we mapped the shared haplotypes of affected fetuses using autozygosity mapping and identified a de novo mutation in the SLC12A1 gene that was associated with hydrallantois in Japanese Black cattle. In kidneys of hydrallantois-affected fetuses, the mutation in SLC12A1 impaired the apical membrane localization of SLC12A1 and reabsorption of Na+-K+-2Cl− in the thick ascending limb of the loop of Henle, leading to a defect in the concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibited polyuria that accumulated in the allantoic cavity. Surveillance of the risk-allele frequency indicated that carriers were not widespread throughout the Japanese Black cattle population. Moreover, we identified the founder individual, and thus could effectively manage the disorder in the population.

Electronic supplementary material: The online version of this article (doi:10.1186/s12864-016-3035-1) contains supplementary material, which is available to authorized users.

No MeSH data available.