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Maternal Primary Carnitine Deficiency and a Novel Solute Carrier Family 22 Member 5 (SLC22A5) Mutation.

ABSTRACT: Primary carnitine deficiency (PCD) is a rare autosomal recessive disorder caused by loss of function mutations in the solute carrier family 22 member 5 (SLC22A5) gene that encodes a high-affinity sodium-ion-dependent organic cation transporter protein (OCTN2). Reduced carnitine transport results in diminished fatty acid oxidation in heart and skeletal muscle and carnitine wasting in urine. We present a case of PCD diagnosed in an adult female after a positive newborn screen (NBS) for PCD that was not confirmed on follow-up testing. The mother was referred for evaluation of persistent fatigue and possible hypothyroidism even though all measurements of thyroid-stimulating hormone were well within the range of 0.4 to 2.5 mIU/L expected for reproductive-age women. She was found to have unequivocally low levels of both total carnitine and carnitine esters, and genetic testing revealed compound heterozygosity for 2 SLC22A5 mutations. One mutation (c.34G>A [p.Gly12Ser]) is a known missense mutation with partial OCTN2 activity, but the other mutation (c.41G>A [p.Trp14Ter]) is previously unreported and results in a premature stop codon and truncated OCTN2. This case illustrates that some maternal inborn errors of metabolism can be identified by NBS and that maternal carnitine levels should be checked after a positive NBS test for PCD.

SUBMITTER: Jakoby M

PROVIDER: S-EPMC8155745 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The human Solute Carrier 22 family (SLC22), also termed the organic ion transporter family, consists of 28 distinct multi-membrane spanning proteins, which phylogenetically cluster together according to their charge specificity for organic cations (OCTs), organic anions (OATs) and organic zwitterion/cations (OCTNs). Some SLC22 family members are well characterized in terms of their substrates, transport mechanisms and expression patterns, as well as their roles in human physiology and pharmacology, whereas others remain orphans with no known ligands. Pharmacologically, SLC22 family members play major roles as determinants of the absorption and disposition of many prescription drugs, and several including the renal transporters, OCT2, OAT1 and OAT3 are targets for many clinically important drug-drug interactions. In addition, mutations in some of these transporters (SLC22A5 (OCTN2) and SLC22A12 (URAT1) lead to rare monogenic disorders. Genetic polymorphisms in SLC22 transporters have been associated with common human disease, drug response and various phenotypic traits. Three members in this family were deorphaned in very recently: SLC22A14, SLC22A15 and SLC22A24, and found to transport specific compounds such as riboflavin (SLC22A14), anti-oxidant zwitterions (SLC22A15) and steroid conjugates (SLC22A24). Their physiologic and pharmacological roles need further investigation. This review aims to summarize the substrates, expression patterns and transporter mechanisms of individual SLC22 family members and their roles in human disease and drug disposition and response. Gaps in our understanding of SLC22 family members are described. Significance Statement In recent years, three members of the SLC22 family of transporters have been deorphaned and found to play important roles in the transport of diverse solutes. New research has furthered our understanding of the mechanisms, pharmacological roles, and clinical impact of SLC22 transporters. This minireview provides overview of SLC22 family members of their physiologic and pharmacologic roles, the impact of genetic variants in the SLC22 family on disease and drug response, and summary of recent studies deorphaning SLC22 family members.

Project description:BackgroundHydrallantois 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.ResultsShared 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).ConclusionsIn 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.

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Maternal Primary Carnitine Deficiency and a Novel Solute Carrier Family 22 Member 5 (SLC22A5) Mutation.

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