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Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.

Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, Shneider BL, Picarsic JL, Jacobson TA, Zhang J, He W, Liu P, Knisely AS, Finegold MJ, Muzny DM, Boerwinkle E, Lupski JR, Plon SE, Gibbs RA, Eng CM, Yang Y, Washington GC, Porteus MH, Berquist WE, Kambham N, Singh RJ, Xia F, Enns GM, Moore DD - Nat Commun (2016)

Bottom Line: Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases.Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism.Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

View Article: PubMed Central - PubMed

Affiliation: Lucile Packard Children's Hospital, Divisions of Medical Genetics, Stanford University Medical Center, Stanford, California 94305, USA.

ABSTRACT
Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

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NR1H4 mutations.(a) Sanger sequencing of the homozygous variant c.526C>T (p.R176*) in patients 1 and 2 of family 1. Both parents are heterozygous carriers. (b) Sequence of the homozygous variant c.419_420insAAA (p.Tyr139_Asn140insLys) in patients 3 and 4 of family 2. The mother carries a heterozygous change. (c) Breakpoint junction mapping in family 2. PCR and Sanger sequencing confirmed a 31.7 kb deletion that spans the first two coding exons of all NR1H4 isoforms. The deletion region is marked with a filled box. (d) All family 2 members except the mother carry this deletion. PCR was performed using forward and reverse primers indicated with arrow heads in d. Primer pair F1/R1b fails to amplify at the wild-type locus because the distance between them exceeds the limit of PCR reaction. Primer pair F1/R1 serves as control. NTC, no template control.
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f2: NR1H4 mutations.(a) Sanger sequencing of the homozygous variant c.526C>T (p.R176*) in patients 1 and 2 of family 1. Both parents are heterozygous carriers. (b) Sequence of the homozygous variant c.419_420insAAA (p.Tyr139_Asn140insLys) in patients 3 and 4 of family 2. The mother carries a heterozygous change. (c) Breakpoint junction mapping in family 2. PCR and Sanger sequencing confirmed a 31.7 kb deletion that spans the first two coding exons of all NR1H4 isoforms. The deletion region is marked with a filled box. (d) All family 2 members except the mother carry this deletion. PCR was performed using forward and reverse primers indicated with arrow heads in d. Primer pair F1/R1b fails to amplify at the wild-type locus because the distance between them exceeds the limit of PCR reaction. Primer pair F1/R1 serves as control. NTC, no template control.

Mentions: Whole-exome sequencing of patient 2 (family 1) identified an apparently homozygous c.526C>T (p.R176*) mutation in NR1H4 that prematurely terminates the protein at amino acid 176 (nucleotide: NM_005123 and protein: NP_005114) in the DNA-binding domain (DBD). The same homozygous mutation was found in patient 1; both asymptomatic parents are carriers (Fig. 2a and Table 2). Consanguinity in this family was confirmed by cSNP array detection of ∼89 Mb of total homozygous regions larger than 5 Mb each in patient 1. The predicted residual protein fragment lacks both DNA binding and hormone receptor domains, and immunohistochemistry showed no FXR expression (Fig. 1). This variant has been reported previously in one patient with infantile cholestasis as a heterozygous change18 but the heterozygous family 1 parents had normal liver biochemistry. The mother did not have symptoms of cholestasis in any of her three pregnancies.


Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.

Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, Shneider BL, Picarsic JL, Jacobson TA, Zhang J, He W, Liu P, Knisely AS, Finegold MJ, Muzny DM, Boerwinkle E, Lupski JR, Plon SE, Gibbs RA, Eng CM, Yang Y, Washington GC, Porteus MH, Berquist WE, Kambham N, Singh RJ, Xia F, Enns GM, Moore DD - Nat Commun (2016)

NR1H4 mutations.(a) Sanger sequencing of the homozygous variant c.526C>T (p.R176*) in patients 1 and 2 of family 1. Both parents are heterozygous carriers. (b) Sequence of the homozygous variant c.419_420insAAA (p.Tyr139_Asn140insLys) in patients 3 and 4 of family 2. The mother carries a heterozygous change. (c) Breakpoint junction mapping in family 2. PCR and Sanger sequencing confirmed a 31.7 kb deletion that spans the first two coding exons of all NR1H4 isoforms. The deletion region is marked with a filled box. (d) All family 2 members except the mother carry this deletion. PCR was performed using forward and reverse primers indicated with arrow heads in d. Primer pair F1/R1b fails to amplify at the wild-type locus because the distance between them exceeds the limit of PCR reaction. Primer pair F1/R1 serves as control. NTC, no template control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4759630&req=5

f2: NR1H4 mutations.(a) Sanger sequencing of the homozygous variant c.526C>T (p.R176*) in patients 1 and 2 of family 1. Both parents are heterozygous carriers. (b) Sequence of the homozygous variant c.419_420insAAA (p.Tyr139_Asn140insLys) in patients 3 and 4 of family 2. The mother carries a heterozygous change. (c) Breakpoint junction mapping in family 2. PCR and Sanger sequencing confirmed a 31.7 kb deletion that spans the first two coding exons of all NR1H4 isoforms. The deletion region is marked with a filled box. (d) All family 2 members except the mother carry this deletion. PCR was performed using forward and reverse primers indicated with arrow heads in d. Primer pair F1/R1b fails to amplify at the wild-type locus because the distance between them exceeds the limit of PCR reaction. Primer pair F1/R1 serves as control. NTC, no template control.
Mentions: Whole-exome sequencing of patient 2 (family 1) identified an apparently homozygous c.526C>T (p.R176*) mutation in NR1H4 that prematurely terminates the protein at amino acid 176 (nucleotide: NM_005123 and protein: NP_005114) in the DNA-binding domain (DBD). The same homozygous mutation was found in patient 1; both asymptomatic parents are carriers (Fig. 2a and Table 2). Consanguinity in this family was confirmed by cSNP array detection of ∼89 Mb of total homozygous regions larger than 5 Mb each in patient 1. The predicted residual protein fragment lacks both DNA binding and hormone receptor domains, and immunohistochemistry showed no FXR expression (Fig. 1). This variant has been reported previously in one patient with infantile cholestasis as a heterozygous change18 but the heterozygous family 1 parents had normal liver biochemistry. The mother did not have symptoms of cholestasis in any of her three pregnancies.

Bottom Line: Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases.Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism.Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

View Article: PubMed Central - PubMed

Affiliation: Lucile Packard Children's Hospital, Divisions of Medical Genetics, Stanford University Medical Center, Stanford, California 94305, USA.

ABSTRACT
Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

Show MeSH
Related in: MedlinePlus