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Novel complex Re-Arrangement ofARG1commonly shared by unrelated

patients with Hyperargininemia

Jafar Mohseni a, Chia Boon Hock a, Che Abdul Razak a, Syah Nor Iman Othman d, Fatemeh Hayati a,Winnie Ong PeiTee c, Muzhirah Haniffa c, Bin Alwi Zilfalil b, Rowani Mohd. Rawi b,Lock-Hock Ngu c, Teguh Haryo Sasongko a,a Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, USM Health Campus, 16150 Kubang Kerian, Kelantan, Malaysiab Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, USM Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia

c Genetic Department, Kuala Lumpur Hospital, 50586 Jalan Pahang, Kuala Lumpur, Malaysiad Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia

a b s t r a c ta r t i c l e i n f o

Article history:

Accepted 23 September 2013

Available online 5 October 2013

Keywords:

Hyperargininemia

Arginase deciency

ARG1

Complex re-arrangement

Background: Hyperargininemiais a very rare progressiveneurometabolicdisorder caused by deciencyof hepatic

cytosolic arginase I, resulting from mutations in the ARG1gene. Until now, some mutations were reported

worldwide and none of them were of Southeast Asian origins. Furthermore, most reported mutations were

point mutations and a few others deletions or insertions.

Objective:This study aims at identifying the disease-causing mutation in theARG1gene of Malaysian patients

with hyperargininemia.

Methodology:We employed a series of PCR amplications anddirect sequencing in order to identifythe mutation.

We subsequently used quantitative real-time PCR to determine the copy number of the exons anking the muta-

tion. We blasted our sequencing data with that of the reference sequence in the NCBI in order to obtain positional

insights of the mutation.Results:We found a novel complex re-arrangement involving insertion, inversion and gross deletion ofARG1

(designated g.insIVS1+1899GTTTTATCAT;g.invIVS1+ 1933_+1953;g.delIVS1+1954_IVS2+ 914;c.del116_188;

p.Pro20SerfsX4) commonly shared by 5 patients with hyperargininemia, each originating from different family.

None of the affected families share known relationship with each other, although four of the ve patients were

known to haverst-cousin consanguineous parents.

Conclusion:This is therst report of complexre-arrangement in theARG1. Furtheranalyses showing thatthe

patientshave shared the samegeographicorigin within the northeasternpart of Malaysia prompted us to suggesta

simple molecular screening of hyperargininemia within related ethnicities using a long-range PCR.

2013 Elsevier B.V. All rights reserved.

1. Introduction

Arginase I is the nal enzyme in the urea cycle that catalyzes thehydrolysis of arginine to urea and ornithine. Arginase I is the product

ofARG1, of which mutations have been described to cause deciency of

the enzyme.ARG1 is located in the long arm of chromosome 6 (6q23)

and is made up of eight exons that code for 322 amino acids (Iyer et al.,

1998).

Hepatic Arginase I Deciency causes hyperargininemia (OMIM #

207800), a rare inborn errors of urea cycle which is inherited in an auto-

somal recessive manner with theincidence of only 1 in 2,000,000 (ScagliaandLee, 2006). Unlike the other inborn errors of urea cycle which usually

present withan acute hyperammonemic crisis, hyperargininemia usually

has a more chronic presentation in later childhood with neurologic

features such as delayed developmental milestones, spastic diplegia,

learning difculties, and epilepsy (Iyer et al., 1998; Lee et al., 2011). The

extreme spasticity observed in this disorder is not found in other urea

cycle defects and the frequent epileptic symptom is seldom related to

episodes of hyperammonemia (Scaglia and Lee, 2006). Some researchers

have suggested thatan accumulation of guanidino compounds thatcould

interfere with GABAergic transmission is the possible pathogenic

mechanism (Lee et al., 2011). Guanidino compounds have been

shown to inhibit the cerebral cortical sodiumpotassium adenosine

triphosphatase (ATPase) of rats at concentrations comparable with

those seen in affected humans (Scaglia et al., 2004). The ATPase is

Gene 533 (2014) 240245

Abbreviations: ARG1, Arginase 1 Gene; ATPase, Adenosine Triphosphatase; DNA,

DeoxyriboNucleic Acid; dNTP, deoxyribuNucleotide TriPhosphate; GABA, Gamma-

AminoButyric Acid; NCBI, National Center for Biotechnology Information; NHLBI,

National Heart, Lung and Blood Institute; OMIM, Online Mendelian Inheritance in Man;

PCR, Polymerase Chain Reaction; qPCR, quantitative real-time PCR; RefSeq, Reference

Sequence; Sdn. Bhd, Sendirian Berhad (Co. Ltd. in Malaysian).

Corresponding author. Tel.: +60 97676794/6796; fax: +60 97658914.

E-mail addresses:[email protected],[email protected]

(T.H. Sasongko).

0378-1119/$ see front matter 2013 Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.gene.2013.09.081

Contents lists available atScienceDirect

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essential to maintenance of the electrochemical gradient of neurons, and

its inhibition may also be involved in the pathogenesis of the seizure

disorder associated with this disease (Mori et al., 1990).

The Human Gene Mutation Database (Stenson, 2009) reportedto date

at least 37 mutations have been identied inARG1 gene among different

populations worldwide. ReportedARG1 mutations were mostlymissense,

with only very few cases involving deletion and/or insertion withoutreported complex re-arrangement (Stenson, 2009). In addition, there

has been no documented evidence of a common ARG1mutation shared

by patients within the same or related ethnicities, thus making it difcult

for simple molecular diagnostic screening (Carvalho et al., 2012; Tsang

et al., 2012; Vockley et al., 1996). Here we reported a novel complex re-

arrangement mutation of ARG1 shared by 5 unrelated patients with

hyperargininemia and suggested a simplemolecular diagnostic screening.

2. Methods

2.1. Patients and DNA Extraction

Six patients were referred to our laboratory in Human Genome Centre

Universiti Sains Malaysia for molecular genetic analyses ofARG1 gene,from Hospital Kuala Lumpur and Hospital Universiti Sains Malaysia. All

patients were of Malay ethnicity. Information on parental origins was ob-

tained through interview. Family pedigree of each patient was analysed

for three generations. Diagnosis of hyperargininemia was established

based on clinical features and laboratory analysis. Informed consent

was taken prior to blood taking. Genomic DNA was extracted from

whole blood using commercially available kit (QIAamp DNA Mini

Blood Extraction).

2.2. Polymerase Chain Reaction and Direct DNA Sequencing

Polymerase Chain Reaction was performed using GeneAmp PCR

System 9700 (Applied Biosystems, Foster City, CA, USA). The primers

for each exon ofARG1gene were synthesized according to sequences as

described previously (Cardoso et al., 1999; Grody et al., 1992; Uchino

et al., 1992).

In order to clarifyamplication failure ofARG1 exon 2, we employed

long-range PCR amplication using two of the primers described previ-

ously; forward primer of 5-TGACTGACTGGAGAGCTCAAG-3 (Uchino

et al., 1992) and reverse primer of 5-ACACAGTTATTCAACAAGACC-3

(Cardoso et al., 1999). The long-range PCR condition was 2 min at 94

C for initial denaturation, followed by 12 sec at 94 C, 30 sec at 60 C

and 15 min at 68 C for 30 cycles and a nal extension done at 68 C

for 7 min. Amplications were performed in 30 L volume containing

1g of genomic DNA, 1X Buffer S, 100 M dNTPs, 1.1M of each primer

and 2 U MaxTaq polymerase (Vivantis Technology, USA) (Fig. 1).

We subsequently designed a series of primers (refer to Fig. 2(B)) in

order to identify the breakpoint deletion based on theARG1genomic

sequence provided in the NCBI Nucleotide Database (accession no.

GI_163954920; RefSeq NG_007086.2; Primers were synthesized by

First Base Laboratories Sdn. Bhd., Malaysia). Direct DNA Sequencing was

done to identify the mutations, using ABI Prism 3100 Genetic Analyzer

(Applied Biosystems, Foster City, CA, USA).

2.3. Real-Time qPCR

In order to provide information on homozygosity of the deletion, we

performed real-time quantitative PCR for identifying the copy number of

exons 1 and 3 which are anking the deleted region. The real-time quan-

titative PCR was performed according to previously described method

(Tran et al., 2008) using LightCycler 1.5 (Roche Diagnostics, Mannheim,

Germany) and Human -actin as reference gene. Eachexperiment used3

serial template dilutions and was done twice (duplicate experiments).

2.4. Bioinformatics Analysis

We used Basic Local Alignment Search Tool (BLAST) provided by the

NCBI Nucleotide Database, 2013(http://blast.ncbi.nlm.nih.gov/Blast.cgi),

in order to obtain positional insights into the deleted segment.

3. Results

3.1. Patients Features

Table 1summarizes the phenotypes, genotypes and other informa-

tion of the patients. All patients showed neurological decits as well as

striking elevation of plasma arginine level. Almost all showed delayed

developmental delay, while one of the patients showed acute infantile

hyperammonemia. All were known to have parental origin from

Kelantan, one state in the north-eastern part of Peninsular Malaysia. All

but one patient were born from rst-cousin consanguineous marriage.

Three-generation pedigree analyses of all the patients showed no rela-

tionship between any families.

3.2. Molecular Genetic Analyses

We initially tried to amplify each of the8 exonsin theARG1of all the

6 patients. In one of the patients [patient ID 002(2)] we successfully

amplied all of the8 exons. Upon direct DNA sequencing, we identied

a nonsense mutation inARG1 exon 8 (Table 1). However, we experi-

enced consistent failure in amplifying exon 2 of the gene for the other

5 patients. We investigated this further by performing long-range PCR

amplication encompassing exon 1 to exon 3, where the amplication

worked well. Our long-range PCR identied a reduction of approximately

2.5 kilobases in the PCR product of the amplied region, which was con-

sistently found in all 5 patients and suggesting a segmental genomic loss

between exon 1 and exon 3 (Fig. 1).

We subsequentlyperformed a seriesof PCR amplications and direct

sequencing to identify the breakpoint of the deletion (Fig. 2A). Upon

Fig. 1.PCR 1 shows the amplication failure of exon 2, which was subsequently claried by PCR 2 that employed long-range primers. PCR 2 shows a notable size reduction in a region

between exon 1 and exon 3 of the patient. Amplication in PCR 2 encompassed exon 1, intron 1, exon 2, intron 2 and exon 3.

241J. Mohseni et al. / Gene 533 (2014) 240245


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identication of the breakpoint, we subjected our nding to BLAST

andnally conrmed a 10-bp insertion and a 21-bp inversion located

at nucleotides +1899 and +1933 to +1953, respectively, downstream

of exon 1 coupled by a 2357-bp deletion starting at the subsequent

nucleotides (Fig. 2C).

We submitted the novel sequence to the NCBI GenBank. The

sequence was assigned an accession number of KF539857.

In order to obtain information on whether both alleles truly carry

a homozygous mutation, we investigated the extent of genomic re-

arrangement in each allele by quantifying the copy number of exons 1

and 3 which are anking the complex re-arrangement. Our real-time

quantitative PCR found that 4 of the patients with inversiondeletioncarried 2 copies of exon 1 and 2 copies of exon 3, suggesting that both

alleles of the gene may harbour the same extent of re-arrangement

(Table 1).

4. Discussion

We postulated that both ARG1mutations found in our cohort of

patients are diseases-causing. The nonsense mutation found in Patient

ID 002(2) will prematurely truncate the protein translation. The

inversiondeletion found in the rest of the patients spanned a total

loss of 73-bp exon 2. This will consequently lead to a frame shift muta-

tion and also truncate the protein translation.

We identied a novel complex re-arrangement ofARG1 gene in 5

unrelated patients with hyperargininemia. All of the 5 patients werefound to share the same mutation, despite coming from unrelated

families, leading us to think that this mutation could be specic to

Malay and related ethnicities of Southeast Asia. In light of the fact that

we found this novel mutation through a simple long-range PCR, it is

plausible to suggest that our method could be applicable for screening

of hyperargininemia among Malay patients in peninsular Malaysia and

other related ethnicities, such as those in the western part of Indonesia

as well as southern Thai.

The fact that all the 5 families originated from one geographic origin

in the northeasternpart of peninsular Malaysia hasalso sparked suspect

of founder phenomenon, where the unrelated families may actually

share the same ancestral family. Althoughit is not possible forus to clarify

if the consanguinity resulted from multiple generations of close

marriages or from single unusually close marriages, our empiricalobservations to local culture of marriage support the notion that the

patients' families belong to a relatively endogamic group of large commu-

nity. Our pedigree analyses, however, could not identify any relations

between the affected families up to 3 generations.

In order to support the suspect of founder phenomenon, we rstly

need to obtain evidence that the mutations were truly homozygous.

We initially identied the complex re-arrangement as a gross deletion

through a simple long-range PCR that reveal a genomic loss between

exon1 and exon3 oftheARG1 gene. Theamplication identieda single

and discrete PCR product, suggesting singlegenomic isoformof the mu-

tation. In spite of that, one might argue that the single amplication

might rather be due to amplication of the allele with shorter deletion

extent. If one other allele carries a larger deletion beyond exon 1 and

exon 3 of the gene, our initial PCR would have not been able to identifythat. The latter situation indicated a compound heterozygous mutation,

unlikely supportive of a founder phenomenon. Here we demonstrated

A

B C

Fig. 2. (A) Illustrativegure ofARG1gene wherethe mutated genomic segment is indicatedin grey andtheprimerpositionsare indicatedin numberedarrows. (B)List ofprimer seriesthat

we designed, with corresponding numbers to the (A). (C) Sequence alignment between that of the mutated and that of the wildtype.

242 J. Mohseni et al. / Gene 533 (2014) 240245


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Table 1

ARG1genotype and phenotype of Malaysian Malay patients with hyperargininemia.

Patient ID

(Family ID)

Sex Age1 Consanguinity Phenotype Genotype Parental origin

Plasma arginine

(mol/L)2Blood ammonia

(mol/L)3Clinical features Mutation Copies of exon 14 Copies of exon 34

001(1) M 11 m Yes 516 52.7 Delayed developmental milestones rst noticed

at 3 months, failure to thrive, feeding difculties,

microcephaly, limbs hypertonia and hyperreexia,

truncal hypotonia

g.insIVS1+1899GTTTTATCAT;

g.invIVS1+1933_+1953;

g.delIVS1+1954_IVS2+914;

c.del116_188;p.Pro20SerfsX4

1.9 0.11 2.1 0.12 Kelantan

002(2) M 5 y Yes 400 212 Mild delayed developmental milestones during infancy,

acute onset left hemiparesis at 5 years old and MRI

brain demonstrated right fronto-parietal infarct, followed

by cognitive regression, progressive spastic diplegia, lost

ambulation at 9 years old

c.929CNT;p.R291X Not done Kelantan

003(3) F 7 y Yes 840 194 Mild delayed developmental milestones during infancy,

an episode of sudden onset of unconsciousness at 4 years old,

recurrent episodes of leg cramp and weakness during febrile

illnesses since 7 years old,

followed by progressive spastic diplegia,

lost ambulation at 10 years old


g.invIVS1+1933_+1953;



2.1 0.12 2 0.05 Kelantan

004(3) M 6 y Yes 434 81 Normal developmental milestones,

sudden onset seizures and altered sensorium at 6 years old


g.invIVS1+1933_+1953;

g.delIVS1 + 1954_IVS2 + 914;


2 0.05 1.95 0.1 Kelantan

005(4) F 3 m Y es 2451 530 Acute hyperammonemia at 3 months old,

subsequently has delayed developmental milestones


g.invIVS1+1933_+1953;



1 .98 0. 14 1. 99 0. 23 K elan tan

006(5) F 2 y No 475 ND Normal developmental milestones,

sudden onset abdominal pain following a high protein meal

at 2 years old, subsequently developed spastic diplegia,

lost ambulation at 6 years old


g.invIVS1+1933_+1953;



N ot e noug h D NA s ampl e Kel an ta n

1At diagnosis. 2Plasma arginine: normal range, 41114mol/L, 3Blood Ammonia: normal range, 1040 mol/L, 4Mean SD taken from 3 serial template dilution each from duplicate experiments.

243

J.Mohsenietal./Gene533(2014)240245


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that our patientscohort carrying the complex re-arrangement showed

normal copies of theanking exons. This may suggest that both alleles

of the gene carry the same mutation, indicating a truly homozygous

mutation. However, we admit that this nding alone is not sufcient

to demonstrate a founder phenomenon for this mutation.

Hyperargininemia is an extremely rare disorder (Scaglia and Lee,

2006). As such, there are only some mutations ofARG1found to date.While most disease-causing mutations were inicted by changes in one

or a few nucleotides of the gene, 2 gross deletions and 1 gross insertion

were reported (Stenson, 2009).

Our further search on other human gene variant databases showed

that there was no report of a more complex genomic re-arrangement

of this gene (Exome Variant Server, 2013; The 1000 Genomes

Project Consortium, 2012). Our report showed the rst genomic re-

arrangement ofARG1 mutation which is commonly shared by a certain

group of Malayethnicity. In addition,this is also therst report ofARG1

mutations among hyperargininemia patients of this ethnicity.

While the genomic re-arrangement is novel and may only be shared

within related ethnicities, another mutation [c.929CNT;p.R291X in

Patient 002(2)] was previously reported in a French-German patient

(Grody et al., 1992). This nonsense mutation affected a CGN trinucleotide(CGA to TGA), which also constituted a CpGdinucleotide. A C-to-Ttransi-

tion in this type of tri-/dinucleotide has been one of the most frequently

reported mutations in several genetic disorders, namely Hemophilia

B (factor IXgene) (Koeberl et al., 1990), Retinoblastoma (RB1gene),

(Cowell et al., 1994) and Neurobromatosis Type 1 (NF1gene), (Krkljus

et al., 1998). In fact, another mutation of the same nature has been

reported inARG1gene, which turned arginine of codon 21 into a trans-

lation stop (c.119CNT;p.R21X) (Cardoso et al., 1999).

Patients with hyperargininemia were typically presented later in life

with chronic and slowly progressingneurological problems (Scaglia and

Lee, 2006). Only very few patients were reported with neonatal or

infantile presentation of hyperammonemia (Jian-Ghai et al., 2011). One

of our patients (005(4)) was presented with acute hyperammonemia

at 3 months of age. This patient carried the same mutation as the other

4 patients in which the clinical manifestation of hyperargininemia

appeared much later in life. This further conrmed the lack of

genotypephenotype correlation in hyperargininemia patients with

ARG1mutations (Martins et al., 2011).

In conclusion, we have identiedfor the rst timea novel inversion

deletion that resulted from a complex re-arrangement ofARG1 gene

commonly shared by a cohort of unrelated Malay patients with

hyperargininemia. Further analyses showing that the patients have

shared the same geographic origin within the northeastern part of

Malaysia prompted us to suggest a simple molecular screening of

hyperargininemia within related ethnicities using a long-range PCR.

Funding statement

This study was supported by the Universiti Sains Malaysia ResearchUniversity Grants (1001/PPSP/812048 and 1001/PPSP/812072) for

Dr. Teguh Haryo Sasongko.

Contributorship statement

Jafar Mohseni: conception and design, acquisition of data, analysis

and interpretation of data, drafting andrevisingthe article forimportant

intellectual content andnal approval of the version to be published.

Chia Boon Hock: acquisition of data, revising the article for important


NorhazahChe Abd. Razak: acquisition of data, revising the article for

important intellectual content and nal approval of the version to be

published.

Syah Nor Iman Othman: acquisition of data, revising the article forimportant intellectual content and nal approval of the version to be

published.

Fatemeh Hayati: acquisition of data, revising the article for important


Winnie Ong PeiTee: acquisition of data, revising the article for im-

portant intellectual content and nal approval of the version to be

published.

Muzhirah Haniffa: acquisition of data, revising the article for impor-

tant intellectual content andnal approval of theversion to be published.Bin Alwi Zilfalil: conception and design, revising the article for


published.

Rowani Mohd. Rawi: conception and design, revising the article for


published.

Ngu Lock Hock: conception and design, acquisition of data, revising

the article for important intellectual content and nal approval of the

version to be published.

Teguh Haryo Sasongko: conception and design, acquisition of data,

analysis and interpretation of data, drafting and revising the article for


published.

What is already known on this topic

Hyperargininemia is caused by mutations inARG1 gene and a number

of mutations have been found. Mutations found were mostly point muta-

tions with few deletions or insertions. There was no simple screening

method for this disorder as no common mutation was found so far.

What this study adds

This study reports for the rst time a complex re-arrangement of

ARG1 commonly found in un-related patients with hyperargininemia.

This suggests a simple screening method for detecting the mutation

among patients with similar ethnicity of the South East Asian.

Conict of interest

The authors declare no conict of interest.

Acknowledgment

The authors are grateful to the patients and their families for their

voluntary cooperationin this report. The authors wish to thank Asso-

ciate Professor Dr. Gan Siew Hua of the Universiti Sains Malaysia and

Dr. Gunadi of the Universitas Gadjah Mada for their inputs after critically

reading the manuscript. The authors also thank the Director General of

Health, Malaysia, for permission to publish the scientic and clinical

data from Ministry of Healths hospital.

References

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