Synergistic heterozygosity in mice with inherited enzyme deficiencies of mitochondrial fatty acid β-oxidation

Schuler, A. Michele; Gower, Barbara A.; Matern, Dietrich; Rinaldo, Piero; Vockley, Jerry; Wood, Philip A.

doi:10.1016/j.ymgme.2004.09.006

Cited by 55 publications

(46 citation statements)

References 15 publications

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“…In addition, there is growing evidence for the concept of synergistic heterozygosity, in which heterozygosity for a reduced-function allele of one gene may produce a severe phenotype in the context of heterozygosity for a mutation in another gene in the same pathway (Vockley et al, 2000). This phenomenon has already been described for mutations in OCTN2 and for other genes involved in fatty acid metabolism (Vockley et al, 2000;Schuler et al, 2005). Thus, persons carrying the reduced-function OCTN2 alleles identified here may be at risk for defects in fatty acid oxidation as a result of these mutations, per se, or may be at increased risk of fatty acid oxidation defects resulting from synergism of OCTN2 mutations with mutations in other genes involved in mitochondrial fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 90%

Functional Genetic Diversity in the High-Affinity Carnitine Transporter OCTN2 (SLC22A5)

et al. 2006

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Systemic carnitine deficiency (SCD) is a rare autosomal recessive disease resulting from defects in the OCTN2 (SLC22A5) gene, which encodes the high-affinity plasma membrane carnitine transporter. Although OCTN2 is fairly well studied in its relationship with SCD, little is known about the carrier frequency of disease-causing alleles of OCTN2, or of more common functional polymorphisms in this gene. To address these issues, we screened for genetic variants in the OCTN2 coding region by direct sequencing of the exons and flanking intronic region of OCTN2 in a large sample (n ϭ 276) of ethnically diverse subjects. In addition, we established lymphoblastoid cell lines from subjects homozygous for either allele of the previously identified promoter region variant, Ϫ207GϾC. We found eight amino acid sequence variants of OCTN2, of which three (Phe17Leu, Leu144Phe, and Pro549Ser) were polymorphic in at least one ethnic group. When assayed for functional activity by expression in human embryonic kidney 293 cells, using as probes both the endogenous substrate (L-carnitine) and the organic cation tetraethylammonium, three variants showed functional differences from the reference OCTN2 (Phe17Leu, Tyr449Asp, Val481Phe; p Ͻ 0.05). Further studies of the Phe17Leu polymorphism showed a reduced V max for L-carnitine transport to approximately 50% of the reference OCTN2. Confocal microscopy studies using an OCTN2-GFP fusion protein showed that Phe17Leu had distinct subcellular localization from the reference OCTN2, with diffuse cytoplasmic retention of Phe17Leu, in contrast to reference OCTN2, which localized specifically to the plasma membrane. Lymphoblasts from subjects homozygous for the Ϫ207G allele showed increased L-carnitine transport compared with the Ϫ207C/C homozygotes (p Ͻ 0.05). This study suggests that although loss-of-function mutations in OCTN2 are likely to be rare, common variants of OCTN2 found in healthy populations may contribute to variation in the disposition of carnitine and some clinically used drugs.

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Section: Discussionmentioning

confidence: 90%

Functional Genetic Diversity in the High-Affinity Carnitine Transporter OCTN2 (SLC22A5)

et al. 2006

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“…These include congenital nonsyndromic hearing impairment (40), human insulin resistance (41,42), inherited disorders of fatty acid b-oxidation (43), and polycystic kidney disease (44). To our knowledge, this is the first description of combined heterozygosity causing any kind of glomerular disease.…”

Section: Discussionmentioning

confidence: 90%

Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin

Huber¹

2006

Journal of Clinical Investigation

143

105

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Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular diagnosis resulting in end-stage renal disease. Defects in several podocyte proteins have been implicated in the etiology of FSGS, including podocin, a-actinin-4, CD2-associated protein (CD2AP), and TRPC6. Despite our growing understanding of genes involved in the pathogenesis of focal segmental sclerosis, the vast majority of patients with this disease, even those with a familial linkage, lack a clear genetic diagnosis. Here, we tested whether combinations of genetic heterozygosity (bigenic heterozygosity) that alone do not result in clinical kidney disease could function together to enhance susceptibility to glomerular damage and FSGS. Combinations of Cd2ap heterozygosity and heterozygosity of either synaptopodin (Synpo) or Fyn proto-oncogene (Fyn) but not kin of IRRE like 1 (Neph1) resulted in spontaneous proteinuria and in FSGS-like glomerular damage. These genetic interactions were also reflected at a functional level, as we found that CD2AP associates with Fyn and Synpo but not with Neph1. This demonstrates that bigenic heterozygosity can lead to FSGS and suggests that combined mutations in 2 or multiple podocyte genes may be a common etiology for glomerular disease. IntroductionFocal segmental glomerulosclerosis (FSGS) is a major cause of endstage renal disease and is increasing in frequency (1). The structure affected in FSGS is the kidney glomerulus, which is composed of capillaries that are involved in the filtration of blood. The diagnosis of FSGS is based on the clinical findings of proteinuria and specific histopathological changes, with areas of glomerular sclerosis and glomerular tuft collapse that are both focal and segmental. Focal refers to the finding that not all glomeruli are affected, and segmental indicates that only a portion of the affected glomerulus is sclerosed. While the etiology of most cases of FSGS is unknown, the heterogeneous nature of these histologic changes suggests that a combination of different factors is involved, including genetic and environmental influences (2, 3).The podocyte, the visceral epithelial cell of the glomerulus, has taken center stage in research on the pathogenesis of FSGS. Genetic studies in both human and mouse reveal that the development of FSGS is initiated by podocyte dysfunction (2). In humans, mutations of the podocyte-specific gene nephrosis 2 homolog, podocin (Nphs2) (encoding podocin) (4), the more ubiquitously expressed cytoskeletal protein a-actinin-4 (5), and the ion channel protein TRPC6 (6, 7) have been shown to impair podocyte function and to cause an inherited form of FSGS. Mouse studies demonstrate that the complete absence of either podocin (8) or a-actinin-4 (9) results not in FSGS but in a severe podocyte dysfunction leading

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“…Exposure to cold is detected by the brain, leading to activation of the sympathetic nervous system, which heavily innervates thermogenic targets such as BAT and skeletal muscle. Fatal hypothermia is 100% in homozygous knockout mice of VLCAD, LCAD, MCAD, and SCAD, whereas "single heterozygous" enzyme-deficient mice are usually cold-tolerant [42]. There was ∼33% fatal hypothermia in double heterozygous with VLCAD/LCAD, LCAD/SCAD, VLCAD/SCAD combinations on a mixed genetic background [42].…”

Section: Discussionmentioning

confidence: 99%

“…Fatal hypothermia is 100% in homozygous knockout mice of VLCAD, LCAD, MCAD, and SCAD, whereas "single heterozygous" enzyme-deficient mice are usually cold-tolerant [42]. There was ∼33% fatal hypothermia in double heterozygous with VLCAD/LCAD, LCAD/SCAD, VLCAD/SCAD combinations on a mixed genetic background [42]. In the current study, it took an extended challenge (4 − 6 hrs), yet significantly more CPT-1b+/− mice developed fatal hypothermia following a 6-hr cold challenge (Fig.…”

Section: Discussionmentioning

confidence: 99%

Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

You

Kerner

et al. 2008

Molecular Genetics and Metabolism

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Carnitine palmitoyltransferase-1 (CPT-1) catalyzes the rate-limiting step of mitochondrial β-oxidation of long chain fatty acids (LCFA), the most abundant fatty acids in mammalian membranes and in energy metabolism. Human deficiency of the muscle isoform CPT-1b is poorly understood. In the current study, embryos with a homozygous knockout of Cpt-1b were lost before embryonic day 9.5 − 11.5. Also, while there were normal percentages of CPT-1b+/−pups born from both male and female CPT-1b+/− mice crossed with wild-type mates, the number of CPT-1b+/− pups from CPT-1b+/− breeding pairs was under-represented (63% of the expected number). Northern blot analysis demonstrated ∼50% Cpt-1b mRNA expression in brown adipose tissue (BAT), heart and skeletal muscles in the CPT-1b+/− male mice. Consistent with tissue-specific expression of Cpt-1b mRNA in muscle but not liver, CPT-1+/− mice had ∼60% CPT-1 activity in skeletal muscle and no change in total liver CPT-1 activity. CPT-1b+/− mice had normal fasting blood glucose concentration. Consistent with expression of CPT-1b in BAT and muscle, ∼7% CPT-1b+/− mice (n=30) developed fatal hypothermia following a 3 hr cold challenge, while none of the CPT-1b+/+ mice (n=30) did. With a prolonged cold challenge (6 hr), significantly more CPT-1b+/− mice developed fatal hypothermia (52% CPT-1b+/− mice vs. 21% CPT-1b+/+ mice), with increased frequency in females of both genotypes (67% female vs. 38% male CPT-1b+/− mice, and 33% female vs. 8% male CPT-1b+/+ mice). Therefore, lethality of homozygous CPT-1b deficiency in the mice is consistent with paucity of human cases.

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Synergistic heterozygosity in mice with inherited enzyme deficiencies of mitochondrial fatty acid β-oxidation

Cited by 55 publications

References 15 publications

Functional Genetic Diversity in the High-Affinity Carnitine Transporter OCTN2 (SLC22A5)

Functional Genetic Diversity in the High-Affinity Carnitine Transporter OCTN2 (SLC22A5)

Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin

Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

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