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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.


Related in: MedlinePlus

Model of hydrallantois in Japanese Black cattle. a SLC12A1 is involved in the countercurrent mechanism in the kidney. In the kidneys of unaffected fetuses (left panel, a), SLC12A1 is localized at the apical membrane in the thick ascending limb of the loop of Henle and serves as a reabsorption molecule of Na+-K+-2Cl− in the tubules. Transportation of Na+ from the intracellular to interstitial spaces by other transporters leads to an increased osmolality in the interstitial space. The increased interstitial osmolality draws water from the descending thin limb, progressively concentrating the primary urine in the tubules. In the affected fetus kidneys (right panel, a), SLC12A1 dislocates from the apical membrane to cytosol, in turn, impairing reabsorption of Na+-K+-2Cl− in the thick limb of the loop of Henle, leading to defective concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibit polyuria. b Fetal urine storage in the allantoic cavity of the uterus. At mid-gestation, excessive volumes of allantoic fluid obstruct the outflow of fetal urine into the allantoic cavity (right panelb, dotted line) due to limited space in the uterus, resulting in hydronephrosis. The maternal abdomen becomes progressively distended and increases the pressure on the internal organs and fetus in the uterus, causing fetal death
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Fig7: Model of hydrallantois in Japanese Black cattle. a SLC12A1 is involved in the countercurrent mechanism in the kidney. In the kidneys of unaffected fetuses (left panel, a), SLC12A1 is localized at the apical membrane in the thick ascending limb of the loop of Henle and serves as a reabsorption molecule of Na+-K+-2Cl− in the tubules. Transportation of Na+ from the intracellular to interstitial spaces by other transporters leads to an increased osmolality in the interstitial space. The increased interstitial osmolality draws water from the descending thin limb, progressively concentrating the primary urine in the tubules. In the affected fetus kidneys (right panel, a), SLC12A1 dislocates from the apical membrane to cytosol, in turn, impairing reabsorption of Na+-K+-2Cl− in the thick limb of the loop of Henle, leading to defective concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibit polyuria. b Fetal urine storage in the allantoic cavity of the uterus. At mid-gestation, excessive volumes of allantoic fluid obstruct the outflow of fetal urine into the allantoic cavity (right panelb, dotted line) due to limited space in the uterus, resulting in hydronephrosis. The maternal abdomen becomes progressively distended and increases the pressure on the internal organs and fetus in the uterus, causing fetal death

Mentions: In kidneys of the normal fetuses, SLC12A1 reabsorbs Na+-K+-2Cl− at the apical membrane in the thick ascending limb of the loop of Henle. Transportation of Na+ from the intracellular to interstitial spaces by other transporters leads to increased osmolality in the interstitial space, which draws water from the descending thin limb, progressively concentrating the primary urine in the tubules (for review, see [21]) (Fig. 7a). In contrast, the fetuses affected with hydrallantois have impaired Na+ reabsorption via dislocation of SLC12A1 from the apical membrane, which wastes Na+ in the urine (Fig. 7a). Consequently, the affected fetuses are defective in concentrating urine and exhibit polyuria (Fig. 7a), which accumulates in the allantoic cavity in the uterus (Fig. 7b). Functional mesonephros are completely developed at the mid-late gestation stage as described by Skydsgaard [13] and references therein; thus, the fetal kidneys produce large amounts of urine from around the mid-gestation stage onwards. Therefore, in the affected fetuses, an excessive volume of allantois fluid from around the mid-gestation stage onwards causes an obstruction to the outflow of fetal urine into the allantoic cavity (Fig. 7b, dotted line), resulting in hydronephrosis in the fetal kidneys (Fig. 1f, h). In 1956, Neal also reported three cases of hydrallantois with hydronephrosis in Ayrshire and Guernsey cattle fetuses [11]. Subsequently, the maternal abdomen becomes progressively distended at mid-gestation (Fig. 1b) and the allantoic fluid increases the pressure on the internal organs and the fetus in the uterus, finally causing fetal death.Fig. 7


A missense mutation in solute carrier family 12, member 1 ( SLC12A1 ) causes hydrallantois in Japanese Black cattle
Model of hydrallantois in Japanese Black cattle. a SLC12A1 is involved in the countercurrent mechanism in the kidney. In the kidneys of unaffected fetuses (left panel, a), SLC12A1 is localized at the apical membrane in the thick ascending limb of the loop of Henle and serves as a reabsorption molecule of Na+-K+-2Cl− in the tubules. Transportation of Na+ from the intracellular to interstitial spaces by other transporters leads to an increased osmolality in the interstitial space. The increased interstitial osmolality draws water from the descending thin limb, progressively concentrating the primary urine in the tubules. In the affected fetus kidneys (right panel, a), SLC12A1 dislocates from the apical membrane to cytosol, in turn, impairing reabsorption of Na+-K+-2Cl− in the thick limb of the loop of Henle, leading to defective concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibit polyuria. b Fetal urine storage in the allantoic cavity of the uterus. At mid-gestation, excessive volumes of allantoic fluid obstruct the outflow of fetal urine into the allantoic cavity (right panelb, dotted line) due to limited space in the uterus, resulting in hydronephrosis. The maternal abdomen becomes progressively distended and increases the pressure on the internal organs and fetus in the uterus, causing fetal death
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Related In: Results  -  Collection

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Fig7: Model of hydrallantois in Japanese Black cattle. a SLC12A1 is involved in the countercurrent mechanism in the kidney. In the kidneys of unaffected fetuses (left panel, a), SLC12A1 is localized at the apical membrane in the thick ascending limb of the loop of Henle and serves as a reabsorption molecule of Na+-K+-2Cl− in the tubules. Transportation of Na+ from the intracellular to interstitial spaces by other transporters leads to an increased osmolality in the interstitial space. The increased interstitial osmolality draws water from the descending thin limb, progressively concentrating the primary urine in the tubules. In the affected fetus kidneys (right panel, a), SLC12A1 dislocates from the apical membrane to cytosol, in turn, impairing reabsorption of Na+-K+-2Cl− in the thick limb of the loop of Henle, leading to defective concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibit polyuria. b Fetal urine storage in the allantoic cavity of the uterus. At mid-gestation, excessive volumes of allantoic fluid obstruct the outflow of fetal urine into the allantoic cavity (right panelb, dotted line) due to limited space in the uterus, resulting in hydronephrosis. The maternal abdomen becomes progressively distended and increases the pressure on the internal organs and fetus in the uterus, causing fetal death
Mentions: In kidneys of the normal fetuses, SLC12A1 reabsorbs Na+-K+-2Cl− at the apical membrane in the thick ascending limb of the loop of Henle. Transportation of Na+ from the intracellular to interstitial spaces by other transporters leads to increased osmolality in the interstitial space, which draws water from the descending thin limb, progressively concentrating the primary urine in the tubules (for review, see [21]) (Fig. 7a). In contrast, the fetuses affected with hydrallantois have impaired Na+ reabsorption via dislocation of SLC12A1 from the apical membrane, which wastes Na+ in the urine (Fig. 7a). Consequently, the affected fetuses are defective in concentrating urine and exhibit polyuria (Fig. 7a), which accumulates in the allantoic cavity in the uterus (Fig. 7b). Functional mesonephros are completely developed at the mid-late gestation stage as described by Skydsgaard [13] and references therein; thus, the fetal kidneys produce large amounts of urine from around the mid-gestation stage onwards. Therefore, in the affected fetuses, an excessive volume of allantois fluid from around the mid-gestation stage onwards causes an obstruction to the outflow of fetal urine into the allantoic cavity (Fig. 7b, dotted line), resulting in hydronephrosis in the fetal kidneys (Fig. 1f, h). In 1956, Neal also reported three cases of hydrallantois with hydronephrosis in Ayrshire and Guernsey cattle fetuses [11]. Subsequently, the maternal abdomen becomes progressively distended at mid-gestation (Fig. 1b) and the allantoic fluid increases the pressure on the internal organs and the fetus in the uterus, finally causing fetal death.Fig. 7

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.


Related in: MedlinePlus