Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia
2015; Elsevier BV; Volume: 97; Issue: 6 Linguagem: Inglês
10.1016/j.ajhg.2015.10.011
ISSN1537-6605
AutoresWolfgang M. Schmidt, S. Lane Rutledge, Rebecca Schüle, Benjamin Mayerhofer, Stephan Züchner, Eugen Boltshauser, Reginald E. Bittner,
Tópico(s)Genetics and Neurodevelopmental Disorders
ResumoHereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome. Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome. Hereditary cerebellar ataxias are genetically heterogeneous disorders characterized by clinically variable gait disturbances and often accompanied by additional neurological symptoms and involvement of other organs. The molecular underpinnings of the vast majority of these disorders still remain widely unknown.1Storey E. Genetic cerebellar ataxias.Semin. Neurol. 2014; 34: 280-292Crossref PubMed Scopus (34) Google Scholar, 2Mancuso M. Orsucci D. Siciliano G. Bonuccelli U. The genetics of ataxia: through the labyrinth of the Minotaur, looking for Ariadne’s thread.J. Neurol. 2014; 261: S528-S541Crossref PubMed Scopus (25) Google Scholar, 3Jayadev S. Bird T.D. Hereditary ataxias: overview.Genet. Med. 2013; 15: 673-683Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 4Anheim M. Tranchant C. Koenig M. The autosomal recessive cerebellar ataxias.N. Engl. J. Med. 2012; 366: 636-646Crossref PubMed Scopus (252) Google Scholar In a previous study, we uncovered the genetic defect underlying the mdf (muscle deficient) mouse by identifying a frame-shifting mutation in Scyl15Schmidt W.M. Kraus C. Höger H. Hochmeister S. Oberndorfer F. Branka M. Bingemann S. Lassmann H. Müller M. Macedo-Souza L.I. et al.Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration.EMBO Rep. 2007; 8: 691-697Crossref PubMed Scopus (54) Google Scholar. Initially, the mdf mouse was considered a murine motor-neuron-disease model, owing to the progressive loss of motor neurons in the spinal cord and brain stem, causing severe neurogenic muscular atrophy.6Blot S. Poirier C. Dreyfus P.A. The mouse mutation muscle deficient (mdf) is characterized by a progressive motoneuron disease.J. Neuropathol. Exp. Neurol. 1995; 54: 812-825Crossref PubMed Scopus (27) Google Scholar Our group refined the mdf phenotype by demonstrating that the mdf mouse is affected by a complex form of spinocerebellar ataxia, characterized by progressive gait ataxia, cerebellar vermis atrophy, Purkinje cell loss, and optic-nerve thinning.5Schmidt W.M. Kraus C. Höger H. Hochmeister S. Oberndorfer F. Branka M. Bingemann S. Lassmann H. Müller M. Macedo-Souza L.I. et al.Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration.EMBO Rep. 2007; 8: 691-697Crossref PubMed Scopus (54) Google Scholar SCYL1 is highly conserved among eukaryotes and belongs to the SCY1-like family of catalytically inactive protein kinases, harboring an N-terminal serine-threonine kinase-like domain,7Liu S.C. Lane W.S. Lienhard G.E. Cloning and preliminary characterization of a 105 kDa protein with an N-terminal kinase-like domain.Biochim. Biophys. Acta. 2000; 1517: 148-152Crossref PubMed Scopus (17) Google Scholar a centrally located HEAT repeat domain, and C-terminal protein-interaction motifs. Recent findings by others have demonstrated that SCYL1 represents an important protein at the interface between the Golgi apparatus and the membrane trafficking machinery mediated by coatomer (COPI)-coated vesicles.8Hamlin J.N. Schroeder L.K. Fotouhi M. Dokainish H. Ioannou M.S. Girard M. Summerfeldt N. Melançon P. McPherson P.S. Scyl1 scaffolds class II Arfs to specific subcomplexes of coatomer through the γ-COP appendage domain.J. Cell Sci. 2014; 127: 1454-1463Crossref PubMed Scopus (32) Google Scholar, 9Burman J.L. Hamlin J.N. McPherson P.S. Scyl1 regulates Golgi morphology.PLoS ONE. 2010; 5: e9537Crossref PubMed Scopus (45) Google Scholar, 10Burman J.L. Bourbonniere L. Philie J. Stroh T. Dejgaard S.Y. Presley J.F. McPherson P.S. Scyl1, mutated in a recessive form of spinocerebellar neurodegeneration, regulates COPI-mediated retrograde traffic.J. Biol. Chem. 2008; 283: 22774-22786Crossref PubMed Scopus (64) Google Scholar Specifically, it has been shown that SCYL1 exerts a crucial role in COPI-mediated retrograde protein trafficking by undergoing oligomerization through the HEAT repeats and interacting with several key components of COPI coats.8Hamlin J.N. Schroeder L.K. Fotouhi M. Dokainish H. Ioannou M.S. Girard M. Summerfeldt N. Melançon P. McPherson P.S. Scyl1 scaffolds class II Arfs to specific subcomplexes of coatomer through the γ-COP appendage domain.J. Cell Sci. 2014; 127: 1454-1463Crossref PubMed Scopus (32) Google Scholar In addition, SCYL1 is a cytoplasmic component of the nuclear tRNA export machinery.11Chafe S.C. Mangroo D. Scyl1 facilitates nuclear tRNA export in mammalian cells by acting at the nuclear pore complex.Mol. Biol. Cell. 2010; 21: 2483-2499Crossref PubMed Scopus (28) Google Scholar Together, this suggests that SCYL1 is involved in vital intracellular transport processes, which might provide a basis for understanding the molecular mechanism underlying disease states caused by loss of SCYL1. Here, we report on two families with three individuals affected by a previously undescribed ataxia syndrome. Informed consent was obtained from all involved individuals (or their parents), and the institutional ethical committees of the participating medical centers (University of Alabama at Birmingham and the University of Miami) approved the study. First, we identified two siblings, a young woman (20 years old, F1:II.2) and her brother (16 years old, F2:II.3), born to unrelated healthy parents of white European descent with British and German roots (family 1), with a strikingly similar clinical phenotype (Table 1). Beginning at the age of 9 months, both siblings presented with recurrent episodes of liver failure mainly triggered by fever. These recurrent and occasionally severe episodes ceased in mid-childhood. However, both were left with chronic residual fibrotic liver disease and pronounced hepatomegaly and concomitant splenomegaly (Figure 1). Neurologically, both siblings had a delay in achieving early motor milestones. Since early childhood, they developed cerebellar dysfunction presenting as gait disturbances (inability to tandem gait, mild balance difficulties, occasional falling) and intention tremor. Additionally, they developed muscle weakness restricted to their lower legs, presenting with foot drop, and numbness, indicative of a hereditary motor and sensory neuropathy. Both individuals are affected by neurogenic stuttering, which is more pronounced in the male sibling, negatively impacting his communication skills (Table 1).Table 1Genetic and Clinical Findings of Individuals with SCYL1 MutationsFamily 1Family 2Individual 1 (F1:II.2)Individual 2 (F1:II.3)Individual 3 (F2:II.1)Age at most recent clinical examination (years)201617GenderfemalemalefemaleDescentEuropeanCubanSCYL1 mutation allele 1c.937delG, p.Val313Cysfs∗6c.1230+1G>A, p.?SCYL1 mutation allele 2c.1509_1510delTG, p.Ala504Profs∗15c.1636C>T, p.Gln546∗HepatologyNo. of recurrent episodes of liver dysfunction (age at first episode to age at last episode)5 (9 months to 11 years)3 (9 months to 6 years)3 (18 months to 3 years)Hepatosplenomegaly+++++Liver biopsy: focal bridging fibrosis+ND+NeurologyWalking independently (months)172412Cognitionnormalmild intellectual disabilitymild learning disabilityNeurogenic stutter (age of onset, years)+ (20)++ (4)++ (3)Cerebellar oculomotor disturbance++saccadic pursuitLimb ataxia (UL/LL)−/−−/−+/+Gait ataxia (onset)+ (early childhood)+ (early childhood)+ (childhood)Distal weaknessLL > ULLL > ULLL > ULMuscle atrophyLL = ULLL = ULLL = ULSensory deficits and symptomsdecreased pain perception (distal LL)NDintermittent distal paresthesias (UL and LL)ElectroneurophysiologyNDNDaxonal PNPStretch reflexesdecreased (LL)decreased (LL)increased (UL > LL)Spasticity−−+ (UL)Hip abductor weakness−−+ (LL, central pattern)Tremorintention (cerebellar)intention (cerebellar)actionMRICerebellar vermis atrophy+++++Optic nerve thinning++NDAbbreviations are as follows: UL, upper limbs; LL, lower limbs; PNP, peripheral neuropathy; ND, not determined; −, not present; +, present (mild); ++, present (pronounced). Open table in a new tab Abbreviations are as follows: UL, upper limbs; LL, lower limbs; PNP, peripheral neuropathy; ND, not determined; −, not present; +, present (mild); ++, present (pronounced). Initial MRI scans were performed at ages 9 (F1:II.3) and 13 years (F1:II.2), respectively, and revealed a selective atrophy of the cerebellar vermis (Figures 2A–2C), which was apparently non-progressive over a follow-up period of 7 years. The hemispheres of the cerebellum appeared normal (Figure 2C). Additionally, thinning of the optic nerves (Figure 2D) was depicted on MRI scans performed at ages 16 (F1:II.3) and 20 (F1:II.2), compatible with subclinical optic atrophy given that both individuals still have well-preserved visual acuity. In the first MRI, measurements of the optic nerves were not possible due to artifacts caused by dental braces. To unravel the genetic etiology of the cerebellar ataxia syndrome in this family, we performed whole-exome sequencing.13Pyle A. Smertenko T. Bargiela D. Griffin H. Duff J. Appleton M. Douroudis K. Pfeffer G. Santibanez-Koref M. Eglon G. et al.Exome sequencing in undiagnosed inherited and sporadic ataxias.Brain. 2015; 138: 276-283Crossref PubMed Scopus (102) Google Scholar, 14Ng S.B. Buckingham K.J. Lee C. Bigham A.W. Tabor H.K. Dent K.M. Huff C.D. Shannon P.T. Jabs E.W. Nickerson D.A. et al.Exome sequencing identifies the cause of a mendelian disorder.Nat. Genet. 2010; 42: 30-35Crossref PubMed Scopus (1484) Google Scholar, 15Choi M. Scholl U.I. Ji W. Liu T. Tikhonova I.R. Zumbo P. Nayir A. Bakkaloğlu A. Ozen S. Sanjad S. et al.Genetic diagnosis by whole exome capture and massively parallel DNA sequencing.Proc. Natl. Acad. Sci. USA. 2009; 106: 19096-19101Crossref PubMed Scopus (1004) Google Scholar DNA libraries were constructed from one affected individual (F1:II.3), both parents (F1.I.1 and F1:I.2), and the unaffected sister (F1:II.1) with the SureSelect XT2 All Exon V4 kit (Agilent). Sequencing (100 bp paired-end reads) was performed by GeneDx on a HiSeq 2000 sequencing system (Illumina). The DNA sequence was mapped to and analyzed against the reference human genome (UCSC Genome Browser hg19; within the targeted coding exons and splice junctions of known protein-coding RefSeq genes, the average depth-of-coverage was 119-fold and 97.8% of the target sequence was covered at least 10-fold). The GeneDx Xome Analyzer software was used to evaluate sequence changes in the affected individual in comparison to changes in other sequenced family members. Whole-exome variant analysis did not yield pathogenic variants in any genes with known ataxia associations, neither in genes currently related to “hereditary ataxia” or in any of the 125 genes associated with “ataxia” in Human Gene Mutation Database (HGMD) entries. However, both affected siblings were found to harbor two mutations within SCYL1 (SCY1-like, kinase-like [MIM: 607982]), c.937delG (p.Val313Cysfs∗6) in exon 7 and c.1509_1510delTG (p.Ala504Profs∗15) in exon 11 (GenBank: NM_020680.3). Neither mutation is represented in large reference datasets, such as 1000 Genomes (October 2014 data release, more than 2,500 individuals), the NHLBI Exome Sequencing Project (ESP) Exome Variant Server (6,500 exomes), or the Exome Aggregation Consortium Browser (ExAc, January 2015 release, encompassing data from more than 60,000 unrelated individuals). SCYL1 mutations in all members of the family were confirmed by PCR and conventional DNA sequencing (PCR protocol and primer sequences are available from the authors on request). The existence of two very rare putative null-mutations in SCYL1, the ortholog of which has been shown to be mutated in the Scyl1mdf/mdf mouse model,5Schmidt W.M. Kraus C. Höger H. Hochmeister S. Oberndorfer F. Branka M. Bingemann S. Lassmann H. Müller M. Macedo-Souza L.I. et al.Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration.EMBO Rep. 2007; 8: 691-697Crossref PubMed Scopus (54) Google Scholar provided strong evidence that disruption of SCYL1 might be the molecular cause of the multisystem disorder in this family. In line with this assumption, we confirmed that both affected siblings are compound heterozygous for the two mutations, whereas both parents are carriers of only one or the other mutation and an unaffected sibling carries neither (Figures 3A–3C). To determine whether disruptive mutations in SCYL1 are causatively related to an autosomal recessively inherited hepatocerebellar ataxia-neuropathy syndrome, we subsequently queried the Genesis (formerly GEM.app) database,16Gonzalez M. Falk M.J. Gai X. Postrel R. Schüle R. Zuchner S. Innovative Genomic Collaboration Using the GENESIS (GEM.app) Platform.Hum. Mutat. 2015; 36: 950-956Crossref PubMed Scopus (72) Google Scholar a collaborative web-platform comprising more than 7,000 whole exomes and 1,200 whole genomes, including ∼5,000 datasets of families with a wide spectrum of neurological disorders. Whole-exome sequencing was performed with the SureSelect Human All Exon 50Mb kit (Agilent) for capture and 120 bp paired-end sequencing on a HiSeq2000 (Illumina). Data analysis was performed with the Genesis (GEM.app) pipeline (the average depth-of-coverage was 77-fold and 85% of the target sequence was covered at least 10-fold). We identified two different formally disruptive SCYL1 mutations in a presently 17-year-old girl (F2:II.1, Table 1) initially diagnosed with Charcot-Marie-Tooth disease. The phenotype bore striking similarities to the two siblings with SCYL1 mutations described above. The girl was born to non-consanguineous parents with at least three generations of Cuban family history (family 2). Between the ages of 18 months and 3 years, she suffered from three episodes of acute liver failure, each brought about by a febrile infection, which left hepatosplenomegaly as a residuum. Liver biopsy performed during one of the acute episodes revealed acute hepatitis with early bridging fibrosis. The first of these episodes was accompanied by a generalized status epilepticus and required artificial respiration for almost three weeks. Although her achievements of motor milestones were reportedly normal, she developed progressive gait problems at age 3, leading to frequent falling and early exhaustion, and a progressively debilitating neurogenic stutter. At age 10, running was barely possible and markedly reduced fine motor coordination was noted. At age 17, a predominant motor peripheral neuropathy, manifested by distally accentuated weakness in the upper and lower limbs, pronounced amyotrophy of the hands and feet, and bilateral pes equinus, dominated the clinical picture. Additionally, mild cerebellar and pyramidal system involvement was noted and a learning disability suspected, although not formally tested. Nerve conduction studies corroborated the diagnosis of a mixed sensorimotor peripheral neuropathy. At age 13, a subtle atrophy of the upper cerebellar vermis was noted on MRI (Figure S1). Measurements of optic nerve diameters were not possible for technical reasons. The SCYL1 mutations identified in this individual, namely a splice-site mutation (c.1230+1G>A [p.?]) affecting the invariable +1 nucleotide of intron 9 (causing disruption of correct mRNA splicing by inducing skipping of exon 9, which encodes part of the HEAT repeat domain, Figure S2) and a premature termination mutation (c.1636C>T [p. Gln546∗]) in exon 12, are predictably deleterious. Neither mutation is referred to in the reference databases mentioned above. Whereas the mother (F2:I.1) is heterozygous for the splice-site mutation, the father (F2:I.2) is heterozygous for the nonsense mutation, indicating compound heterozygosity (Figures 3D–3F). In the next step, we probed dermal fibroblasts of the affected individuals and their parents (family 1) to determine the amounts of SCYL1 by using two antibodies directed against the C and N termini of SCYL1.5Schmidt W.M. Kraus C. Höger H. Hochmeister S. Oberndorfer F. Branka M. Bingemann S. Lassmann H. Müller M. Macedo-Souza L.I. et al.Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration.EMBO Rep. 2007; 8: 691-697Crossref PubMed Scopus (54) Google Scholar In contrast to the normal amount of SCYL1 detected in fibroblasts from both parents, there was a complete loss of SCYL1 in fibroblasts from both affected individuals, as revealed by western blotting (Figure 4A) and immunofluorescence experiments (Figures 4B and 4C). SCYL1-knockdown in vitro experiments in HeLa cells suggested a role of SCYL1 in context with the integrity of the Golgi apparatus.8Hamlin J.N. Schroeder L.K. Fotouhi M. Dokainish H. Ioannou M.S. Girard M. Summerfeldt N. Melançon P. McPherson P.S. Scyl1 scaffolds class II Arfs to specific subcomplexes of coatomer through the γ-COP appendage domain.J. Cell Sci. 2014; 127: 1454-1463Crossref PubMed Scopus (32) Google Scholar, 9Burman J.L. Hamlin J.N. McPherson P.S. Scyl1 regulates Golgi morphology.PLoS ONE. 2010; 5: e9537Crossref PubMed Scopus (45) Google Scholar Therefore, we measured the surface area of the Golgi in dermal fibroblasts derived from affected individuals and their parents and found the Golgi to be massively enlarged in SCYL1-negative cells (Figures 5A–5C). These data indicate that SCYL1 is indeed a regulator of Golgi morphology not only in HeLa cells in knockdown experiments,9Burman J.L. Hamlin J.N. McPherson P.S. Scyl1 regulates Golgi morphology.PLoS ONE. 2010; 5: e9537Crossref PubMed Scopus (45) Google Scholar but also in primary human fibroblasts affected by naturally occurring, disruptive mutations of SCYL1. The clinical manifestations of the disease in the individuals described in this study overlap to a large extent with the phenotype of the Scyl1mdf/mdf mouse model. Cerebellar ataxia accompanied by cerebellar vermis atrophy, motor-predominant peripheral neuropathy, and optic-nerve thinning are consistent neurological features in both mice and humans. Whereas peripheral neuropathy and distal muscular atrophy predominate in individual F2:II.1, cerebellar ataxia represents the most striking phenotype in both siblings in family 1 (F1:II.2 and F1:II.3). However, neurogenic stuttering, optic-nerve thinning and upper motor neuron dysfunction suggest a more widespread SCYL1-associated clinical and pathologic phenotype. Intriguingly, although all three affected individuals reported here presented with severe recurrent episodes of acute liver failure in infancy, no such episodes or corresponding phenotypes have been observed in the Scyl1mdf/mdf mouse so far, warranting more in-depth investigations regarding this in the mouse model. Collectively, our data provide compelling evidence that disruptive mutations in SCYL1 cause a syndrome characterized by early-onset episodes of acute liver failure, cerebellar ataxia, and peripheral motor and sensory neuropathy in humans. It is probable that the SCYL1 mutations identified here represent the more severe end of the mutational landscape. Other lesions, such as missense mutations, which do not fully abrogate SCYL1 function, might be associated with a variable clinical picture. The description of other individuals with SCYL1 mutations has to be awaited, which will allow the capture of a foreseeably-wide clinical spectrum of manifestations. Our findings add SCYL1 to a list of several other genes implicated in disorders involving the cerebellum, whose gene products are implicated in the Golgi network.17Di Gregorio E. Borroni B. Giorgio E. Lacerenza D. Ferrero M. Lo Buono N. Ragusa N. Mancini C. Gaussen M. Calcia A. et al.ELOVL5 mutations cause spinocerebellar ataxia 38.Am. J. Hum. Genet. 2014; 95: 209-217Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 18Corbett M.A. Schwake M. Bahlo M. Dibbens L.M. Lin M. Gandolfo L.C. Vears D.F. O’Sullivan J.D. Robertson T. Bayly M.A. et al.A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia.Am. J. Hum. Genet. 2011; 88: 657-663Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 19Senderek J. Krieger M. Stendel C. Bergmann C. Moser M. Breitbach-Faller N. Rudnik-Schöneborn S. Blaschek A. Wolf N.I. Harting I. et al.Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy.Nat. Genet. 2005; 37: 1312-1314Crossref PubMed Scopus (194) Google Scholar Several causes for hereditary infantile liver failure are currently known. Interestingly, mutations in MARS (MIM: 156560) and LARS (MIM: 151350), both encoding tRNA synthetases, are associated with multisystem manifestations involving transient infantile hepatopathy.20van Meel E. Wegner D.J. Cliften P. Willing M.C. White F.V. Kornfeld S. Cole F.S. Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype.BMC Med. Genet. 2013; 14: 106Crossref PubMed Scopus (51) Google Scholar, 21Casey J.P. McGettigan P. Lynam-Lennon N. McDermott M. Regan R. Conroy J. Bourke B. O’Sullivan J. Crushell E. Lynch S. Ennis S. Identification of a mutation in LARS as a novel cause of infantile hepatopathy.Mol. Genet. Metab. 2012; 106: 351-358Crossref PubMed Scopus (65) Google Scholar Although speculative, the functional role of SCYL1 in nuclear-cytoplasmic tRNA transport might therefore be related to the molecular mechanism behind the transient liver failure shared by all three individuals with SCYL1 mutations in this study. Notably, mutations in NBAS (MIM: 608025), encoding a protein that is apparently involved in retrograde transport from the Golgi to the ER, were recently shown to cause early-onset recurrent acute liver failure (infantile liver failure syndrome 2, ILFS2 [MIM: 616483])22Haack T.B. Staufner C. Köpke M.G. Straub B.K. Kölker S. Thiel C. Freisinger P. Baric I. McKiernan P.J. Dikow N. et al.Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy.Am. J. Hum. Genet. 2015; 97: 163-169Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar or a multisystem disorder involving infantile liver failure.23Garcia Segarra N. Ballhausen D. Crawford H. Perreau M. Campos-Xavier B. van Spaendonck-Zwarts K. Vermeer C. Russo M. Zambelli P.Y. Stevenson B. et al.NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina.Am. J. Med. Genet. A. 2015; (Published online August 19, 2015)https://doi.org/10.1002/ajmg.a.37338Crossref PubMed Scopus (51) Google Scholar Because SCYL1 was also shown to be involved in a similar Golgi-ER-pathway,10Burman J.L. Bourbonniere L. Philie J. Stroh T. Dejgaard S.Y. Presley J.F. McPherson P.S. Scyl1, mutated in a recessive form of spinocerebellar neurodegeneration, regulates COPI-mediated retrograde traffic.J. Biol. Chem. 2008; 283: 22774-22786Crossref PubMed Scopus (64) Google Scholar it is tempting to speculate that dysfunction of the Golgi-ER transport function might represent a common pathogenic mechanism, which underlies severe recurrent episodes of acute liver failure in infancy. These parallels warrant further studies to investigate how loss of SCYL1 can cause liver failure. Once more, this study demonstrates that molecular genetics and pre-clinical research on mouse models is capable of propelling the identification and understanding of the corresponding human disease24Longman C. Brockington M. Torelli S. Jimenez-Mallebrera C. Kennedy C. Khalil N. Feng L. Saran R.K. Voit T. Merlini L. et al.Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan.Hum. Mol. Genet. 2003; 12: 2853-2861Crossref PubMed Scopus (380) Google Scholar, 25Grewal P.K. Holzfeind P.J. Bittner R.E. Hewitt J.E. Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse.Nat. Genet. 2001; 28: 151-154Crossref PubMed Scopus (278) Google Scholar and strongly argues for an unbiased exome-wide strategy in the molecular diagnosis of individuals affected by rare inherited disorders. The authors are grateful for the participation of the affected individuals and their parents in this study. The authors thank David R. Kelly, M.D. (Pathologist-in-Chief and Medical Director of Laboratories, Children’s of Alabama, Birmingham, AL and Clinical Professor of Pathology, University of Alabama at Birmingham) for pathological expertise, Lisa Abreu, Feifei Tao, and Cima Saghira (Hussman Institute for Human Genomics, University of Miami) for coordination of clinical data collection and assistance in molecular genetic analysis, and Jennifer Reichbauer (Hertie Institute for Clinical Brain Research, University of Tübingen) for RNA analysis in family 2. The authors thank Ludger Schöls, M.D. (Hertie-Institute for Clinical Brain Research and German Research Center for Neurodegenerative Diseases) for establishing the research cooperation that finally led to identification of the third individual with SCYL1 mutations. This study was supported by the Interdisciplinary Center for Clinical Research Tübingen (grant 1970-0-0 to R.S.), the European Union (grant PIOF-GA-2012-326681 “HSP/CMT genetics” to R.S.), E-RARE grants of the German Ministry for Education and Research to the NEUROLIPID project (01GM1408B to R.S.), and the NIH (grants 5R01NS072248, 1R01NS075764, and 5R01NS054132 to S.Z.). Download .pdf (.49 MB) Help with pdf files Document S1. Figures S1 and S2 The URLs for data presented herein are as follows:1000 Genomes, http://browser.1000genomes.orgExAC Browser, http://exac.broadinstitute.org/GenBank, http://www.ncbi.nlm.nih.gov/genbank/HGMD Professional, http://www.biobase-international.com/product/hgmdNHLBI Exome Sequencing Project (ESP) Exome Variant Server, http://evs.gs.washington.edu/EVS/OMIM, http://www.omim.org/UCSC Genome Browser, http://genome.ucsc.edu
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