JIMD Reports, Volume 23

128 Pages·2015·5.044 MB·English

by  Johannes Zschocke, Matthias Baumgartner, Eva Morava, Marc Patterson, Shamima Rahman, Verena Peters (eds.)

Johannes Zschocke
Matthias Baumgartner
Eva Morava
Marc Patterson
Shamima Rahman
Verena Peters Editors
JIMD Repor ts
Volume 23
JIMD Reports
Volume 23
.
Johannes Zschocke
Editor-in-Chief
Matthias Baumgartner Eva Morava
(cid:129) (cid:129)
Marc Patterson Shamima Rahman
(cid:129)
Editors
Verena Peters
Managing Editor
JIMD Reports
Volume 23
Editor-in-Chief Editor
JohannesZschocke MarcPatterson
DivisionofHumanGenetics DivisionofChildandAdolescent
MedicalUniversityInnsbruck Neurology
Innsbruck MayoClinic
Austria Rochester
Minnesota
Editor USA
MatthiasBaumgartner
DivisionofMetabolismandChildren’sResearchCentre Editor
UniversityChildren’sHospitalZurich ShamimaRahman
Zurich ClinicalandMolecularGeneticsUnit
Switzerland UCLInstituteofChildHealth
London
Editor UK
EvaMorava
TulaneUniversityMedicalSchool ManagingEditor
NewOrleans VerenaPeters
Louisiana CenterforChildandAdolescent
USA Medicine
HeidelbergUniversityHospital
Heidelberg
Germany
ISSN2192-8304 ISSN2192-8312 (electronic)
JIMDReports
ISBN978-3-662-47466-2 ISBN978-3-662-47467-9 (eBook)
DOI10.1007/978-3-662-47467-9
SpringerHeidelbergNewYorkDordrechtLondon
#SSIEMandSpringer-VerlagBerlinHeidelberg2015
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Contents
ArginineFunctionallyImprovesClinicallyRelevantHumanGalactose-1-Phosphate
Uridylyltransferase(GALT)VariantsExpressedinaProkaryoticModel......... 1
AnaI.Coelho,MatildeTrabuco,MariaJoa˜oSilva,IsabelTavaresdeAlmeida,
PaulaLeandro,IsabelRivera,andJoa˜oB.Vicente
EffectandTolerabilityofAgalsidaseAlfainPatientswithFabryDiseaseWhoWere
TreatmentNa¨ıveorFormerlyTreatedwithAgalsidaseBetaorAgalsidaseAlfa ... 7
OzlemGoker-Alpan,KhanNedd,SumaP.Shankar,Yeong-HauH.Lien,NealWeinreb,
AnnaWijatyk,PeterChang,andRickMartin
Niemann-PickTypeC-2Disease:IdentificationbyAnalysisofPlasma
Cholestane-3b,5a,6b-TriolandFurtherInsightintotheClinicalPhenotype ..... 17
J.Reunert,A.S.Lotz-Havla,G.Polo,F.Kannenberg,M.Fobker,M.Griese,E.Mengel,
A.C.Muntau,P.Schnabel,O.Sommerburg,I.Borggraefe,A.Dardis,A.P.Burlina,
M.A.Mall,G.Ciana,B.Bembi,A.B.Burlina,andT.Marquardt
TheModulatoryEffectsofthePolymorphismsinGLA50-UntranslatedRegion
UponGeneExpressionAreCell-TypeSpecific ............................. 27
SusanaFerreira,CarlosReguenga,andJoa˜oPauloOliveira
®
TheKuvan AdultMaternalPaediatricEuropeanRegistry(KAMPER)
MultinationalObservationalStudy:Baselineand1-YearDatainPhenylketonuria
PatientsResponsivetoSapropterin...................................... 35
FriedrichK.Trefz,AniaC.Muntau,FlorianB.Lagler,FlavieMoreau,JanAlm,
AlbertoBurlina,FrankRutsch,AmayaBe´langer-Quintana,andFranc¸oisFeillet
PostmortemFindingsandClinicalCorrelatesinIndividualswithInfantile-Onset
PompeDisease ...................................................... 45
LorenD.M.Pena,AlanD.Proia,andPriyaS.Kishnani
ClinicalSeverityofPGK1DeficiencyDueToaNovelp.E120KSubstitutionIs
ExacerbatedbyCo-inheritanceofaSubclinicalTranslocationt(3;14)(q26.33;q12),
DisruptingNUBPLGene .............................................. 55
Dezso˝ David,L´ıgiaS.Almeida,MaristellaMaggi,CarlosArau´jo,StefanImreh,
GiovannaValentini,Gyo¨rgyFekete,andIre´nHaltrich
AbnormalNewbornScreeninginaHealthyInfantofaMotherwith
UndiagnosedMedium-ChainAcyl-CoADehydrogenaseDeficiency............. 67
LiseAksglaede,MetteChristensen,JessH.Olesen,MortenDuno,RikkeK.J.Olsen,
BrageS.Andresen,DavidM.Hougaard,andAllanM.Lund
v
vi Contents
CobalaminCDiseaseMissedbyNewbornScreeninginaPatientwithLow
CarnitineLevel...................................................... 71
RebeccaC.Ahrens-Nicklas,EsraSerdaroglu,ColleenMuraresku,andCanFicicioglu
AdverseEffectsofGenisteininaMucopolysaccharidosisTypeIMouseModel ... 77
SandraD.K.Kingma,TomWagemans,LodewijkIJlst,JurgenSeppen,
MarionJ.J.Gijbels,FritsA.Wijburg,andNaomivanVlies
ExpandingtheClinicalandMagneticResonanceSpectrumofLeukoencephalopathy
withThalamusandBrainstemInvolvementandHighLactate(LTBL)inaPatient
HarboringaNovelEARS2Mutation..................................... 85
RobertaBiancheri,EleonoraLamantea,MariasavinaSeverino,DariaDiodato,Marina
Pedemonte,DeniseCassandrini,AlexandraPloederl,FedericaTrucco,ChiaraFiorillo,
CarloMinetti,FilippoM.Santorelli,MassimoZeviani,andClaudioBruno
MitochondrialDNADepletionandDeletionsinPaediatricPatientswith
NeuromuscularDiseases:NovelPhenotypes ............................... 91
TuomasKomulainen,Milla-RiikkaHautakangas,ReettaHinttala,SallaPakanen,
VesaVa¨ha¨sarja,PetriLehenkari,Pa¨iviOlsen,Pa¨iviVieira,OutiSaarenpa¨a¨-Heikkila¨,
JohannaPalmio,HannuTuominen,PietariKinnunen,KariMajamaa,HeikkiRantala,
andJohannaUusimaa
Medium-ChainAcyl-CoADehydrogenaseDeficiency:EvaluationofGenotype-
PhenotypeCorrelationinPatientsDetectedbyNewbornScreening ........... 101
GwendolynGramer,GiselaHaege,JunminFang-Hoffmann,GeorgF.Hoffmann,
ClausR.Bartram,KatrinHinderhofer,PeterBurgard,andMartinLindner
Rhabdomyolysis-AssociatedMutationsinHumanLPIN1LeadtoLossof
PhosphatidicAcidPhosphohydrolaseActivity ............................ 113
GeorgeG.Schweitzer,SaraL.Collier,ZhoujiChen,JamesM.Eaton,
AnneM.Connolly,RobertC.Bucelli,AlanPestronk,ThurlE.Harris,
andBrianN.Finck
Dup-24bpintheCHIT1GeneinSixMexicanAmerindianPopulations........ 123
T.D.DaSilva-Jose´,K.J.Jua´rez-Rendo´n,J.A.Jua´rez-Osuna,A.Porras-Dorantes,
A.Valladares-Salgado,M.Cruz,M.Gonzalez-Ibarra,A.G.Soto,M.T.Magan˜a-Torres,
L.Sandoval-Ram´ırez,and Jose´ El´ıasGarc´ıa-Ortiz
JIMDReports
DOI10.1007/8904_2015_420
RESEARCH REPORT
Arginine Functionally Improves Clinically Relevant Human
Galactose-1-Phosphate Uridylyltransferase (GALT)
Variants Expressed in a Prokaryotic Model
Ana I. Coelho(cid:129)Matilde Trabuco(cid:129)Maria João Silva(cid:129)
Isabel Tavares de Almeida(cid:129)Paula Leandro(cid:129)
Isabel Rivera(cid:129)João B. Vicente
Received:30October2014/Revised:28January2015/Accepted:09February2015/Publishedonline:27March2015
#SSIEMandSpringer-VerlagBerlinHeidelberg2015
Abstract Classic galactosemia is a rare genetic disease of Furthermore, it revealed that arginine presents a mutation-
the galactose metabolism, resulting from deficient activity specific beneficial effect, particularly on the prevalent
of galactose-1-phosphate uridylyltransferase (GALT). The p.Q188R and p.K285N variants, which led us to hypothe-
current standard of care is lifelong dietary restriction of sizethatitmightconstituteapromisingtherapeuticagentin
galactose, which however fails to prevent the development classic galactosemia.
of long-term complications. Structural-functional studies
demonstrated that the most prevalent GALT mutations give Introduction
rise to proteins with increased propensity to aggregate in
solution. Arginine is a known stabilizer of aggregation- Classic galactosemia (OMIM #230400) is a rare metabolic
prone proteins, having already shown a beneficial effect in disease resulting from deficient activity of galactose-1-
other inherited metabolic disorders. phosphate uridylyltransferase (GALT, EC 2.7.7.12), the
Herein we developed a prokaryotic model of galactose second enzyme of the Leloir pathway (Fridovich-Keil and
sensitivity that allows evaluating in a cellular context the Walter 2008). This inherited metabolic disorder is a
mutations’ impact on GALT function, as well as the potentially lethal disease that develops in the neonatal
potential effect of arginine in functionally rescuing clini- period, upon exposure to galactose in milk (Berry and
cally relevant variants. Walter2012; Fridovich-Keil and Walter 2008).The present
This study revealed that some hGALT variants, previ- standard of care is a lifelong galactose-restricted diet,
ously described to exhibit no detectable activity in vitro, which, notwithstanding its irrefutable life-saving role in
actually present residual activity when determined in vivo. the neonatal period, fails to prevent long-term cognitive,
motor, and fertility impairments (Bosch 2006; Fridovich-
Keil and Walter 2008; Waggoner et al. 1990), and thus
Communicatedby:GerardT.Berry,M.D. intenseresearchhasbeendedicatedtothepursuitofamore
Competinginterests:Nonedeclared effective therapy.
: : : :
A.I.Coelho: M.Trabu:co M.J.Silva I.T.deAlmeida ClassicgalactosemiaiscausedbymutationsintheGALT
P.Leandro I.Rivera J.B.Vicente(*) gene, and more than 260 variations have already been
MetabolismandGeneticsGroup,ResearchInstituteforMedicines described, the majority being missense mutations (>60%)
(iMed.ULisboa),FacultyofPharmacy,UniversityofLisbon,
(Calderon et al. 2007; Leslie et al. 1992). Structural and
1649-003Lisbon,Portugal
e-mail:[email protected] functional studies demonstrated that clinically relevant
: : : :
GALT mutations result in misfolded protein variants
M.J.Silva I.T.deAlmeida P.Leandro I.Rivera J.B.Vicente
DepartmentofBiochemistryandHumanBiology,Facultyof (Coelho et al. 2014; McCorvie et al. 2013). A decrease in
Pharmacy,UniversityofLisbon,1649-003Lisbon,Portugal thermal and conformational stability has been observed for
A.I.Coelho severalGALTvariants(McCorvieetal.2013),althoughthe
DepartmentofPediatrics/LaboratoryofGeneticMetabolicDiseases, most frequent GALT mutations actually affect the variants’
MaastrichtUniversityMedicalCenter,6202Maastricht,
aggregation propensity, particularly the p.Q188R variant,
TheNetherlands
2 JIMDReports
responsible for >60% of galactosemic phenotypes (Coelho Table 1 Cell culture conditions to evaluate the ability of GALT
variantstoalleviategalactosetoxicityandtheeffectofarginine
et al. 2014; Suzuki et al. 2001).
Argininehasbeenpreviouslydescribed astherapeutically Supplementationa
beneficial for a pyruvate dehydrogenase complex-deficient
patient whose biochemical and clinical symptoms signifi- Galactose Arginine
cantly improved upon arginine aspartate intake (Silva et al.
I (cid:3) (cid:3)
2009). A positive roleof argininehas also been observed in
II + (cid:3)
the peroxisome function of cultured cells from peroxisome
III (cid:3) +
biogenesis disorder patients with mutations in PEX1, PEX6,
IV + +
andPEX12(Berendseetal.2013).Furthermore,arginineisa
long-recognized protein stabilizer that has been proposed to
aAll cultures were grown in M9 minimal medium containing 1%
exert an anti-aggregation effect by increasing the activation glycerolascarbonsource,supplementedwith100mMferroussulfate
energy of protein aggregation (Baynes et al. 2005). In line and100mMzincsulfate
with this, we sought to evaluate whether arginine exerts a
protectivestabilizingeffecttowardsclinicallyrelevantGALT
variants.Accordingly,thisstudyaimedtoevaluatetheeffect a starting optical density at 600 nm (OD ) of 0.05. At
600nm
of arginine on rescuing variant GALT function and alleviat- OD600nm ¼ 0.3, 250 mM isopropyl-D-thiogalactoside
ing galactose-induced toxicity in a prokaryotic model of (IPTG) was added to all cultures to induce protein
galactose sensitivity. expression, as well as 25 mM arginine to cultures III and
IV (Table 1).After 1 hofproteinexpression induction,1%
galactose was added to cultures II and IV (Table 1).
Materials and Methods Cultures growth was followed by hourly measurements of
OD ,startingatinductiontime(t ¼ 0h)andupto9h.
600nm
Cloning and Mutagenesis Growth curves were obtained from plotting OD
600nm
from cultures I and II (Table 1) as a function of time
The Escherichia (E.) coli K-12DgalT strain (JW0741-1;D (Figs. 1, 2, and 3 show representative graphics from
galT730::kan), with a deletion of the endogenous galT multiple independent experiments). To directly evaluate
gene, was purchased from the Coli Genetic Stock Center the arginine effect on the rescue from galactose toxicity,
(Baba et al. 2006). The human GALT (hGALT) cDNA ratios r and r were calculated according to Eqs. (1) and
arg
sequence, including an N-terminal hexa-histidyl tag-encod- (2), respectively, and were plotted as a function of time
ing sequence, was cut from the pET24b-based construct (Figs. 2 and 3 show representative graphics from multiple
reported in (Coelho et al. 2014) with the BamHI and independent experiments). Recombinant production of
HindIII restriction enzymes and cloned into the pTrcHisA hGALT and hPAH was confirmed by immunoblotting
expression vector (Invitrogen). The mutations originating analysis, using, respectively, the anti-GALT and anti-His
the studied variants (p.S135L, p.G175D, p.P185S, primary antibodies (sc-365577, Santa Cruz Biotechnology;
p.Q188R, p.R231C, pR231H, p.K285N, and p.N314D) 27-4710-01, GE Healthcare Biosciences).
wereintroducedbysite-directedmutagenesis,aspreviously
described (Coelho et al. 2014), and confirmed by direct r ¼ OD600nmgalðIIÞ ; ð1Þ
sequencing. As a negative control, we employed a OD600nmglyðIÞ
pTrcHisA-based vector containing the cDNA encoding the
OD galþargðIVÞ
human enzyme phenylalanine hydroxylase (hPAH) (Lean- r ¼ 600nm : ð2Þ
arg OD glyþargðIIIÞ
dro et al. 2000). 600nm
Cell Cultures and Growth Media
Results and Discussion
Non-transformed and wild-type hGALT-transformed E. coli
DgalT were first grown in M9 minimal medium (Maniatis We have developed a prokaryotic model of galactose
et al. 1982) containing either 1% glucose (with or without sensitivity using the E. coli DgalT strain, with a deletion
1% galactose), 1% glycerol, or 1% galactose as carbon oftheendogenousgalTgene(Babaetal.2006).Expressing
sources, to evaluate the ability of wild-type hGALT to hGALT variants in this E. coli strain, and assaying the
alleviate galactose toxicity. cultures sensitivity to galactose in the culture medium,
Cultures expressing all hGALT variants and hPAH were allows evaluating the mutations severity in a cellular
grown at 37(cid:1)C in M9 minimal medium (Maniatis et al. context, as well as testing stabilizing compounds. Previous
1982)containingglycerol(1%)assolecarbonsource,from studies reported a yeast model of galactose sensitivity
JIMDReports 3
Fig.1 GalactosetoxicityisalleviatedbyexpressionofhumanGALT. was induced with 250 mM IPTG. After 1 h, vehicle (water, full
Growth profiles of Escherichia coli DgalT transformed with vectors squares)or1%galactose(hollowsquares)wasaddedtothecultures,
encoding wild-type hGALT (Panel a, positive control) or wild-type andthegrowthwasfollowedbyhourlymeasurementsofOD up
600nm
hPAH (Panel b, negative control), in the absence or presence of to 9 h. Growth curves are representative graphics from several
galactose.Bacteriaweregrownat37(cid:1)CinM9minimalmediumwith independent experiments (n¼12 for wild-type hGALTand n¼12
1% glycerol as carbon source. At OD =0.3, protein expression forPAH)
600nm
Fig. 2 Arginine improves the function of p.Q188R, p.K285N, and (water) wasadded tothecultures. Panelsb,d, andfdepict theratio
p.G175DhGALT.GrowthprofilesofEscherichiacoliDgalTexpress- curves for bacteria expressing, respectively, p.Q188R, p.K285N, and
ingthep.Q188R,p.K285N,andp.G175DhGALTvariants(Panelsa, p.G175D hGALT, obtained by dividing, at each time point, the
c, and e, respectively) in the absence or presence of galactose. OD inthepresenceorabsenceofgalactose(blackcircles,inthe
600nm
Bacteria were grown at 37(cid:1)C in M9 minimal medium with 1% presenceof25mMarginine;hollowcircles,absenceofarginine).The
glycerol as carbon source. At OD =0.3, protein expression was gray-shadedareasandthewhitearrowsdepicttheeffectofarginine
600nm
inducedwith250mMIPTG.After1h,vehicle(water,fullsquares)or inimprovingtheabilityofthesevariantstoalleviategalactosetoxicity,
1% galactose (hollow squares) was added to the cultures, and the highlighted by white arrows. Growth curves are representative
growthwasfollowedbyhourlymeasurementsofOD upto9h. graphics from several independent experiments (n¼4 for p.Q188R
600nm
Simultaneously with water/galactose, 25 mM arginine or vehicle andn¼3forp.G175Dandp.K285N)
(Riehman et al. 2001; Ross et al. 2004), which is however carbon source and galactose represents no toxicity in the
technicallymoredemandingandtime-consumingcompara- presence of this hexose. This absent toxicity of galactose
tively to E. coli. likely results from carbon catabolite repression exerted by
glucose,whichrepressesthegalactoseuptakesystemsGalP
Effect of Carbon Sources upon the Growth of Non- and Mgl (G€orke and St€ulke 2008; Misko et al. 1987;
transformed and Wild-Type hGALT-Transformed E. coli Shimizu 2013; Steinsiek and Bettenbrock 2012). In the
DgalT presence of glycerol, transported into E. coli through
facilitated diffusion (Chu et al. 2002), the growth rate was
Non-transformed and wild-type hGALT-transformed E. coli approximately half of that observed in the presence of
DgalT were initially grown in the presence of different glucose, confirming that this polyol is not as efficient as
carbonsources.Fornon-transformedE.coliDgalTcultured glucose as a carbon source, as previously described (Chu
under glucose or glucose plus galactose, the growth curves et al. 2002). In the presence of galactose, the growth was
were indistinguishable, since glucose is the preferred practically arrested, indicating the inability of this strain to