Novel splice‐site mutation in <scp><i>ATP8B1</i></scp> results in atypical <scp>P</scp>rogressive <scp>F</scp>amilial <scp>I</scp>ntrahepatic <scp>C</scp>holestasis <scp>T</scp>ype 1

Copeland, Emily; Renault, Nicolas; Dyack, Sarah; Bulman, Dennis E.; Bedard, Karen; Otley, Anthony; Magee, Fergall; Acott, Philip D.; Greer, Wenda L.

doi:10.1111/j.1440-1746.2012.07290.x

Cited by 7 publications

(6 citation statements)

References 17 publications

(22 reference statements)

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“…Interestingly, a homozygous splice site mutation preceding exon 16 of the ATP8B1 gene was previously reported in multiple affected individuals within another family with atypical PFIC1. The clinical presentation was similar to that of our patient, with an initial diagnosis of Alagille syndrome and clinical features including bile duct paucity, cardiac defects and renal tubular acidosis [Copeland et al, ]. The finding of mutations in ATP8B1 in these two families suggests that there may be a wider spectrum of disease resulting from defects in this gene, associated with previously unrecognized extrahepatic manifestations.…”

Section: To the Editorsupporting

confidence: 76%

Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation‐negative patient with clinically diagnosed Alagille syndrome

Grochowski

Rajagopalan

Falsey

et al. 2015

American J of Med Genetics Pt A

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Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by bile duct paucity in combination with five primary clinical findings, including cholestasis, cardiac abnormalities (most commonly peripheral pulmonary stenosis or tetralogy of Fallot), skeletal malformations (most commonly butterfly vertebrae or other mild vertebral anomalies), ocular abnormalities (most commonly posterior embryotoxon), and characteristic facial features. Other affected systems include the kidney and vasculature, with anomalies occurring at lower frequency than in the five primary systems. Prior to the availability of genetic testing, ALGS was diagnosed clinically in individuals with bile duct paucity plus at least three of the five primary findings. The frequency of identifiable genetic mutations in ALGS patients with a clinically consistent diagnosis is high, with JAGGED1 (JAG1) mutations identified in 94% and NOTCH2 mutations in 2% of patients.We report on a female patient who presented in infancy with four out of five clinical features of ALGS, including bile duct paucity and resultant cholestasis, a cardiac murmur, posterior embryotoxon and facial features consistent with ALGS after examination by experienced clinical members of our team. These facial features included a high broad forehead, deep-set eyes and a triangular face constituting the characteristic facial features of ALGS. These findings led to a clinical diagnosis of ALGS (syndromic bile duct paucity). Echocardiography was normal by report and to our knowledge, no further cardiac workup was carried out. The patient was not reported to have butterfly vertebrae, but results of spine radiographs were not available for review. She was evaluated at our institution at age 7, at which time her main complaints were failure to thrive and severe pruritus refractory to multiple medications. At that time, her weight was 13.2 kg (< 3rd centile; 50th centile for 2.5 years) and height was 99.8 cm (< 3rd centile; 50th centile for 4 years). Laboratory testing done at that time revealed slightly elevated total bilirubin (1.7 mg/dl; normal range 0.6-1.4 mg/dl) and cholesterol (227 mg/dl; normal range 109-189 mg/dl). Liver enzymes were normal except for a gamma glutamyl transferase How to Cite this Article:Grochowski CM, Rajagopalan R, Falsey AM, Loomes KM, Piccoli DA, Krantz ID, Devoto M, Spinner NB. 2015. Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation-negative patient with clinically diagnosed alagille syndrome. Am J Med Genet Part A 167A:891-893.

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Section: To the Editorsupporting

confidence: 76%

Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation‐negative patient with clinically diagnosed Alagille syndrome

Grochowski

Rajagopalan

Falsey

et al. 2015

American J of Med Genetics Pt A

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“…Furthermore, modifier genes have become increasingly recognized as an important source of phenotypic variation. Since the initiation of this study, another two intronic variants (c.1819+1G>A and c.1820‐1G>C) were reported that were not included . The latter was already characterized by using RNA from Epstein‐Barr virus–transformed lymphocytes from affected individuals and also caused missplicing resulting in a 4‐bp deletion from the 5' end of exon 16.…”

Section: Discussionmentioning

confidence: 99%

“…Since the initiation of this study, another two intronic variants (c.181911G>A and c.1820-1G>C) were reported that were not included. 24,25 The latter was already characterized by using RNA from Epstein-Barr virus-transformed lymphocytes from affected individuals and also caused missplicing resulting in a 4-bp deletion from the 5' end of exon 16. As for most of the variants studied here, this frameshift will lead to a premature stop codon, likely resulting in mRNA and/or protein degradation.…”

Section: Discussionmentioning

confidence: 99%

Analysis of aberrant pre‐messenger RNA splicing resulting from mutations in ATP8B1 and efficient in vitro rescue by adapted U1 small nuclear RNA

et al. 2015

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ATP8B1 deficiency is a severe autosomal recessive liver disease resulting from mutations in the ATP8B1 gene characterized by a continuous phenotypical spectrum from intermittent (benign recurrent intrahepatic cholestasis; BRIC) to progressive familial intrahepatic cholestasis (PFIC). Current therapeutic options are insufficient, and elucidating the molecular consequences of mutations could lead to personalized mutation-specific therapies. We investigated the effect on pre-messenger RNA splicing of 14 ATP8B1 mutations at exon-intron boundaries using an in vitro minigene system. Eleven mutations, mostly associated with a PFIC phenotype, resulted in aberrant splicing and a complete absence of correctly spliced product. In contrast, three mutations led to partially correct splicing and were associated with a BRIC phenotype. These findings indicate an inverse correlation between the level of correctly spliced product and disease severity. Expression of modified U1 small nuclear RNAs (snRNA) complementary to the splice donor sites strongly improved or completely rescued splicing for several ATP8B1 mutations located at donor, as well as acceptor, splice sites. In one case, we also evaluated exon-specific U1 snRNAs that, by targeting nonconserved intronic sequences, might reduce possible off-target events. Although very effective in correcting exon skipping, they also induced retention of the short downstream intron. Conclusion: We systematically characterized the molecular consequences of 14 ATP8B1 mutations at exon-intron boundaries associated with ATP8B1 deficiency and found that the majority resulted in total exon skipping. The amount of correctly spliced product inversely correlated with disease severity. Compensatory modified U1 snRNAs, complementary to mutated donor splice sites, were able to improve exon definition very efficiently and could be a novel therapeutic strategy in ATP8B1 deficiency as well as other genetic diseases. (HEPATOLOGY 2015;61:1382-1391 A TP8B1 deficiency is an autosomal recessive liver disease caused by mutations in ATP8B1, encoding a P-type ATPase. 1 ATP8B1 is expressed in different tissues, such as the liver, stomach, small intestine, pancreas, and cochlea, and is localized on the apical membrane of epithelial cells. 2 The exact role of ATP8B1 is still under investigation, but it seems to be essential for maintaining membrane lipid asymmetry by translocation of aminophospholipids from the outer to the inner leaflet of the plasma

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“…If left untreated, PFIC1 may progress to liver fibrosis, cirrhosis and devastating end‐stage liver failure, eventually requiring liver transplantation in some cases. 2 , 3 , 4 , 5 , 6 The ATP8B1 gene is located on chromosome 18q21‐22 and encodes the familial intrahepatic cholestasis 1 (FIC1) protein, a P‐type ATPase in the P4 family that is involved in bile acid homeostasis and plays a critical role in bile secretion. 1 , 3 , 5 , 7 When the function of FIC1 is impaired due to ATP8B1 gene mutation, bile acids can accumulate, thus injure the hepatocytes and lead to cholestasis in PFIC1.…”

Section: Figurementioning

confidence: 99%

Two novel ATP8B1 mutations involved in progressive familial intrahepatic cholestasis type 1 that is ameliorated by rifampicin: A case report

Huang

Luo

et al. 2022

J of Digest Diseases

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Novel splice‐site mutation in ATP8B1 results in atypical Progressive Familial Intrahepatic Cholestasis Type 1

Abstract: This work expands the phenotypic spectrum of PFIC1, and highlights the overlap in clinical phenotype between Alagille syndrome and PFIC1. Knowledge of the causative mutation allows for carrier testing and prenatal diagnosis in this community.

Cited by 7 publications

References 17 publications

Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation‐negative patient with clinically diagnosed Alagille syndrome

Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation‐negative patient with clinically diagnosed Alagille syndrome

Analysis of aberrant pre‐messenger RNA splicing resulting from mutations in ATP8B1 and efficient in vitro rescue by adapted U1 small nuclear RNA

Two novel ATP8B1 mutations involved in progressive familial intrahepatic cholestasis type 1 that is ameliorated by rifampicin: A case report

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