<i>ACOX2</i>
            deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

Vilarinho, Sílvia; Sarı, Sinan; Mazzacuva, Francesca; Bilgüvar, Kaya; Esendagli-Yilmaz, Guldal; Jain, Dhanpat; Akyol, Gülen; Dalgıç, Buket; Günel, Murat; Clayton, Peter T.; Lifton, Richard P.

doi:10.1073/pnas.1613228113

Cited by 71 publications

(52 citation statements)

References 24 publications

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“…Undiagnosed liver disease remains an unmet medical need in pediatric and adult hepatology, including cholestasis of unknown etiology. We and others have shown the utility of unbiased whole‐exome sequencing (WES) in diagnosing patients with atypical presentations of known liver disorders as well as in identifying novel Mendelian forms of liver diseases. Identification of underlying genetic defects provides new insight into the role of specific genes in the maintenance of normal liver function as well as disease pathogenesis; this finding also identifies potential new therapeutic options for affected patients.…”

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confidence: 99%

Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

et al. 2019

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Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children with high gamma‐glutamyltransferase (GGT) cholestasis. Here, we report whole‐exome sequencing of germline DNA from 2 unrelated children, both offspring of consanguineous union, with neonatal cholestasis and high GGT of unclear etiology. Both children had a rare homozygous damaging mutation (p.Arg219* and p.Val204Met) in kinesin family member 12 ( KIF12 ). Furthermore, an older sibling of the child homozygous for p.Val204Met missense mutation, who was also found to have cholestasis, had the same homozygous mutation, thus identifying the cause of the underlying liver disease. Conclusion : Our findings implicate rare homozygous mutations in KIF12 in the pathogenesis of cholestatic liver disease with high GGT in 3 previously undiagnosed children.

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confidence: 99%

Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

et al. 2019

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“…A recent PNAS paper by Vilarinho et al (1) on ACOX2 deficiency in an 8-y-old male with elevated transaminase levels identifies a homozygous nonsense mutation (p.Y69*) that generates a truncated protein. Inheritance of this mutation was shown to be responsible for a significant elevation in bile acid intermediates in this child.…”

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confidence: 99%

ACOX2 deficiency in primary malignant cardiac tumors

Zhou

Wang

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Since one assumes that both substrates (with a methyl branch in α‐position of the carboxy group) rely on the same β‐oxidation enzymes, either the involved enzymes, including ACOX2, are expressed, some ACOX3, which can desaturate long‐chain 2‐methylbranched fatty acyl‐CoAs but not cholestanoyl‐CoA, is present in mouse intestine, or an alternative pathway is active. The normal pristanic acid levels in an ACOX2 patient support indeed an ACOX2‐independent pristanic acid degradation, and Schulz and coworkers showed that 2‐methylhexadecanoic acid is (partly) shortened by isolated mitochondria. However, the degradation profiles for palmitic acid and its 2‐methylbranched analogue differ along the intestinal tract, excluding a merely mitochondrial process.…”

Section: Resultsmentioning

confidence: 79%

Differential activities of peroxisomes along the mouse intestinal epithelium

Morvay

Baes

Veldhoven

2017

Cell Biochemistry & Function

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The presence of peroxisomes in mammalian intestine has been revealed formerly by catalase staining combined with electron microscopy. Despite the central role of intestine in lipid uptake and the established importance of peroxisomes in different lipid-related pathways, few data are available on the physiological role of peroxisomes in intestinal metabolism, more specifically, α-, β-oxidation, and etherlipid synthesis. Hence, the peroxisomal compartment was analyzed in more detail in mouse intestine. On the basis of immunohistochemistry, the organelles are mainly confined to the epithelial cells. The expression of the classical peroxisome marker catalase was highest in the proximal part of jejunum and decreased along the tract. PEX14 showed a similar profile, but was still substantial expressed in large intestinal epithelium. Immunoblotting of epithelial cells, isolated from the different segments, showed also such gradient for some enzymes, ie, catalase, ACOX1, and D-specific multifunctional protein 2, and for the ABCD1 transporter, being high in small and low or absent in large intestine. Other peroxisomal enzymes (PHYH, HACL1, and ACAA1), the ABCD2 and ABCD3 transporters, and peroxins PEX13 and PEX14, however, did not follow this pattern, displaying rather constant signals throughout the intestinal epithelium. The small intestine displayed the highest peroxisomal β-oxidation activity and is particularly active on dicarboxylic acids. Etherlipid synthesis was high in the large intestine, and colonic cells had the highest content of plasmalogens. Overall, these data suggest that peroxisomes exert different functions according to the intestinal segment.

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ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

Cited by 71 publications

References 24 publications

Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

ACOX2 deficiency in primary malignant cardiac tumors

Differential activities of peroxisomes along the mouse intestinal epithelium

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