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Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

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Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. / Felzen, Antonia; van Wessel, Daan B E; Gonzales, Emmanuel; Thompson, Richard J; Jankowska, Irena; Shneider, Benjamin L; Sokal, Etienne; Grammatikopoulos, Tassos; Kadaristiana, Agustina; Jacquemin, Emmanuel; Spraul, Anne; Lipiński, Patryk; Czubkowski, Piotr; Rock, Nathalie; Shagrani, Mohammad; Broering, Dieter; Nicastro, Emanuele; Kelly, Deirdre; Nebbia, Gabriella; Arnell, Henrik; Fischler, Björn; Hulscher, Jan B F; Serranti, Daniele; Arikan, Cigdem; Polat, Esra; Debray, Dominique; Lacaille, Florence; Goncalves, Cristina; Hierro, Loreto; Muñoz Bartolo, Gema; Mozer-Glassberg, Yael; Azaz, Amer; Brecelj, Jernej; Dezsőfi, Antal; Calvo, Pier Luigi; Grabhorn, Enke; Hartleif, Steffen; van der Woerd, Wendy J; Kamath, Binita M; Wang, Jian-She; Li, Liting; Durmaz, Özlem; Kerkar, Nanda; Jørgensen, Marianne Hørby; Fischer, Ryan; Jimenez-Rivera, Carolina; Alam, Seema; Cananzi, Mara; Laverdure, Noemie; Ferreira, Cristina Targa; Guerrero, Felipe Ordoñez; Wang, Heng; Sency, Valerie; Kim, Kyung Mo; Chen, Huey-Ling; de Carvalho, Elisa; Fabre, Alexandre; Bernabeu, Jesus Quintero; Zellos, Aglaia; Alonso, Estella M; Sokol, Ronald J; Suchy, Frederick J; Loomes, Kathleen M; McKiernan, Patrick J; Rosenthal, Philip; Turmelle, Yumirle; Horslen, Simon; Schwarz, Kathleen; Bezerra, Jorge A; Wang, Kasper; Hansen, Bettina E; Verkade, Henkjan J; NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium.

In: JHEP REP, Vol. 5, No. 2, 02.2023, p. 100626.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Felzen, A, van Wessel, DBE, Gonzales, E, Thompson, RJ, Jankowska, I, Shneider, BL, Sokal, E, Grammatikopoulos, T, Kadaristiana, A, Jacquemin, E, Spraul, A, Lipiński, P, Czubkowski, P, Rock, N, Shagrani, M, Broering, D, Nicastro, E, Kelly, D, Nebbia, G, Arnell, H, Fischler, B, Hulscher, JBF, Serranti, D, Arikan, C, Polat, E, Debray, D, Lacaille, F, Goncalves, C, Hierro, L, Muñoz Bartolo, G, Mozer-Glassberg, Y, Azaz, A, Brecelj, J, Dezsőfi, A, Calvo, PL, Grabhorn, E, Hartleif, S, van der Woerd, WJ, Kamath, BM, Wang, J-S, Li, L, Durmaz, Ö, Kerkar, N, Jørgensen, MH, Fischer, R, Jimenez-Rivera, C, Alam, S, Cananzi, M, Laverdure, N, Ferreira, CT, Guerrero, FO, Wang, H, Sency, V, Kim, KM, Chen, H-L, de Carvalho, E, Fabre, A, Bernabeu, JQ, Zellos, A, Alonso, EM, Sokol, RJ, Suchy, FJ, Loomes, KM, McKiernan, PJ, Rosenthal, P, Turmelle, Y, Horslen, S, Schwarz, K, Bezerra, JA, Wang, K, Hansen, BE, Verkade, HJ & NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium 2023, 'Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency', JHEP REP, vol. 5, no. 2, pp. 100626. https://doi.org/10.1016/j.jhepr.2022.100626

APA

Felzen, A., van Wessel, D. B. E., Gonzales, E., Thompson, R. J., Jankowska, I., Shneider, B. L., Sokal, E., Grammatikopoulos, T., Kadaristiana, A., Jacquemin, E., Spraul, A., Lipiński, P., Czubkowski, P., Rock, N., Shagrani, M., Broering, D., Nicastro, E., Kelly, D., Nebbia, G., ... NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium (2023). Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. JHEP REP, 5(2), 100626. https://doi.org/10.1016/j.jhepr.2022.100626

Vancouver

Felzen A, van Wessel DBE, Gonzales E, Thompson RJ, Jankowska I, Shneider BL et al. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. JHEP REP. 2023 Feb;5(2):100626. https://doi.org/10.1016/j.jhepr.2022.100626

Bibtex

@article{29017408c331491d9778273ab9cb8ef8,
title = "Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency",
abstract = "BACKGROUND & AIMS: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship.METHODS: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS.RESULTS: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001).CONCLUSIONS: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment.IMPACT AND IMPLICATIONS: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.",
author = "Antonia Felzen and {van Wessel}, {Daan B E} and Emmanuel Gonzales and Thompson, {Richard J} and Irena Jankowska and Shneider, {Benjamin L} and Etienne Sokal and Tassos Grammatikopoulos and Agustina Kadaristiana and Emmanuel Jacquemin and Anne Spraul and Patryk Lipi{\'n}ski and Piotr Czubkowski and Nathalie Rock and Mohammad Shagrani and Dieter Broering and Emanuele Nicastro and Deirdre Kelly and Gabriella Nebbia and Henrik Arnell and Bj{\"o}rn Fischler and Hulscher, {Jan B F} and Daniele Serranti and Cigdem Arikan and Esra Polat and Dominique Debray and Florence Lacaille and Cristina Goncalves and Loreto Hierro and {Mu{\~n}oz Bartolo}, Gema and Yael Mozer-Glassberg and Amer Azaz and Jernej Brecelj and Antal Dezs{\H o}fi and Calvo, {Pier Luigi} and Enke Grabhorn and Steffen Hartleif and {van der Woerd}, {Wendy J} and Kamath, {Binita M} and Jian-She Wang and Liting Li and {\"O}zlem Durmaz and Nanda Kerkar and J{\o}rgensen, {Marianne H{\o}rby} and Ryan Fischer and Carolina Jimenez-Rivera and Seema Alam and Mara Cananzi and Noemie Laverdure and Ferreira, {Cristina Targa} and Guerrero, {Felipe Ordo{\~n}ez} and Heng Wang and Valerie Sency and Kim, {Kyung Mo} and Huey-Ling Chen and {de Carvalho}, Elisa and Alexandre Fabre and Bernabeu, {Jesus Quintero} and Aglaia Zellos and Alonso, {Estella M} and Sokol, {Ronald J} and Suchy, {Frederick J} and Loomes, {Kathleen M} and McKiernan, {Patrick J} and Philip Rosenthal and Yumirle Turmelle and Simon Horslen and Kathleen Schwarz and Bezerra, {Jorge A} and Kasper Wang and Hansen, {Bettina E} and Verkade, {Henkjan J} and {NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium}",
note = "{\textcopyright} 2022 The Author(s).",
year = "2023",
month = feb,
doi = "10.1016/j.jhepr.2022.100626",
language = "English",
volume = "5",
pages = "100626",
journal = "JHEP REP",
issn = "2589-5559",
publisher = "Elsevier",
number = "2",

}

RIS

TY - JOUR

T1 - Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

AU - Felzen, Antonia

AU - van Wessel, Daan B E

AU - Gonzales, Emmanuel

AU - Thompson, Richard J

AU - Jankowska, Irena

AU - Shneider, Benjamin L

AU - Sokal, Etienne

AU - Grammatikopoulos, Tassos

AU - Kadaristiana, Agustina

AU - Jacquemin, Emmanuel

AU - Spraul, Anne

AU - Lipiński, Patryk

AU - Czubkowski, Piotr

AU - Rock, Nathalie

AU - Shagrani, Mohammad

AU - Broering, Dieter

AU - Nicastro, Emanuele

AU - Kelly, Deirdre

AU - Nebbia, Gabriella

AU - Arnell, Henrik

AU - Fischler, Björn

AU - Hulscher, Jan B F

AU - Serranti, Daniele

AU - Arikan, Cigdem

AU - Polat, Esra

AU - Debray, Dominique

AU - Lacaille, Florence

AU - Goncalves, Cristina

AU - Hierro, Loreto

AU - Muñoz Bartolo, Gema

AU - Mozer-Glassberg, Yael

AU - Azaz, Amer

AU - Brecelj, Jernej

AU - Dezsőfi, Antal

AU - Calvo, Pier Luigi

AU - Grabhorn, Enke

AU - Hartleif, Steffen

AU - van der Woerd, Wendy J

AU - Kamath, Binita M

AU - Wang, Jian-She

AU - Li, Liting

AU - Durmaz, Özlem

AU - Kerkar, Nanda

AU - Jørgensen, Marianne Hørby

AU - Fischer, Ryan

AU - Jimenez-Rivera, Carolina

AU - Alam, Seema

AU - Cananzi, Mara

AU - Laverdure, Noemie

AU - Ferreira, Cristina Targa

AU - Guerrero, Felipe Ordoñez

AU - Wang, Heng

AU - Sency, Valerie

AU - Kim, Kyung Mo

AU - Chen, Huey-Ling

AU - de Carvalho, Elisa

AU - Fabre, Alexandre

AU - Bernabeu, Jesus Quintero

AU - Zellos, Aglaia

AU - Alonso, Estella M

AU - Sokol, Ronald J

AU - Suchy, Frederick J

AU - Loomes, Kathleen M

AU - McKiernan, Patrick J

AU - Rosenthal, Philip

AU - Turmelle, Yumirle

AU - Horslen, Simon

AU - Schwarz, Kathleen

AU - Bezerra, Jorge A

AU - Wang, Kasper

AU - Hansen, Bettina E

AU - Verkade, Henkjan J

AU - NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium

N1 - © 2022 The Author(s).

PY - 2023/2

Y1 - 2023/2

N2 - BACKGROUND & AIMS: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship.METHODS: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS.RESULTS: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001).CONCLUSIONS: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment.IMPACT AND IMPLICATIONS: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

AB - BACKGROUND & AIMS: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship.METHODS: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS.RESULTS: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001).CONCLUSIONS: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment.IMPACT AND IMPLICATIONS: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

U2 - 10.1016/j.jhepr.2022.100626

DO - 10.1016/j.jhepr.2022.100626

M3 - SCORING: Journal article

C2 - 36687469

VL - 5

SP - 100626

JO - JHEP REP

JF - JHEP REP

SN - 2589-5559

IS - 2

ER -