Γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in ggt1

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Γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in ggt1"


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ABSTRACT γ-Glutamyl transpeptidase deficiency (glutathionuria, OMIM 231950) is a rare disease, with only six patients reported in the literature, although this condition has probably been


underdiagnosed due the difficulty to routinely analyze glutathione in clinical samples and to the fact that no genetic defect has been coupled to the disease so far. We report two siblings


with mild psychomotor developmental delay and mild neurological symptoms, who presented a markedly increased excretion of glutathione in urine and a very low γ-glutamyl transpeptidase


activity in serum. Whole-genome sequencing revealed the presence of a 16.9 kb homozygous deletion in _GGT1_, one of the genes encoding enzymes with γ-glutamyl transpeptidase activity in the


human genome. Close analysis revealed the presence of a 13 bp insertion at the deletion junction. This is the first report of a genetic variant as the cause of glutathionuria. In addition,


genetic characterization of the patients’ parents and a healthy sibling has provided direct genetic evidence regarding the autosomal recessive nature of this disease. You have full access to


this article via your institution. Download PDF SIMILAR CONTENT BEING VIEWED BY OTHERS NOVEL _CLTC_ VARIANTS CAUSE NEW BRAIN AND KIDNEY PHENOTYPES Article 07 July 2021 NOVEL BIALLELIC


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_SLC5A6_-RELATED DISORDERS Article 27 November 2023 INTRODUCTION Glutathionuria (OMIM 231950) is caused by a defect in γ-glutamyl transpeptidase (γ-GT, EC 2.3.2.2.), the enzyme that cleaves


the γ-glutamyl bond of glutathione (GSH, γ-l-glutamyl-l-cysteinylglycine) to produce cysteinylglycine and glutamate [1]. GSH is the most abundant non-protein thiol compound in cells and as


such it has an important role in antioxidant defense, xenobiotic detoxification, maintenance of redox homeostasis, and cell signaling via _S_-glutathionylation of proteins such as receptors,


protein kinases, and transcription factors. GSH is also a substrate for the synthesis of eicosanoids. For excellent extensive reviews on the biological functions of GSH, see references [2,


3,]. The first patient with glutathionuria was described in 1971, although a previous possible case is cited [4]. To the present day, only six patients from four families have been reported


[5,6,7,8,9,10,11]. Most patients presented involvement of the central nervous system in the form of moderate mental retardation, behavioral disturbance, and, in one case, seizures [8].


Marfanoid features were observed in two siblings [11]. Age of diagnosis ranged from the second to the sixth decade of life. In none of these cases was the genetic cause of glutathionuria


identified. See Table 1 for a summary of clinical and biochemical features of all patients reported in the literature. Several genes are potentially involved in the expression of enzymes


with γ-GT activity in humans [12]. _GGT1_, the best characterized, encodes an extracellular enzyme anchored to the plasma membrane of cells that is highly efficient in the cleavage of the


γ-glutamyl bond of oxidized and reduced GSH, as well as leukotriene C4, whereas the product of _GGT5_ acts mostly on reduced GSH and leukotriene C4, albeit less efficiently than the product


of _GGT1_ [13]. _GGT2_ expresses an inactive protein, due to its inability to undergo the autoproteolytic cleavage to produce a large and a small subunit, which is essential for the


catalytic activity of γ-GTs [14]. Very little is known about _GGT6_ and _GGT7_. The latter, highly expressed in the brain, has been recently involved in the progression of glioblastoma [15].


Two other genes, _GGTLC1_ and _GGTLC2_, have the potential to encode the light chain of γ-GT. In addition, according to NCBI (National Center for Biotechnology Information), four


pseudogenes sharing homology with _GGT1_ are present in the human genome, namely _GGT3P_, _GGTLC5P_, _GGT8P_, and _GGT4P_. Here we report two siblings with glutathionuria caused by a large


homozygous deletion in _GGT1_. This is, to our knowledge, the first report that links a genetic defect to this condition. MATERIAL/SUBJECTS AND METHODS PATIENTS’ CLINICAL DESCRIPTION PATIENT


1 This boy is the third child to healthy parents of Turkish origin. He has a healthy older brother and an affected older sister (Patient 2). He was born at term after a normal gestation.


Birth weight was 2,840 g (− 2 SD), length was 48 cm (− 1.5 SD), and head circumference was 34 cm (− 1.5 SD). The APGAR score was 9–10–10 and the perinatal period was uncomplicated. The


psychomotor development was delayed and he started to say single words and to walk unsupported at 2 years of age. There has been no regression. At the age of 10 years, the patient was first


referred to us for investigations because of suspected mental retardation. Psychological testing at 11 years of age revealed moderate learning disability and the boy has attended special


school. He has been healthy except for day and nighttime urinary incontinence, mild constipation, and treatment because of atopic rhinoconjunctivitis, eczema, and asthma bronchiale. Clinical


examination at 11 years of age revealed mild hypotelorism and low-seated ears. He had mild ataxia upon walking, intention tremor, mild dysdiadochokinesis, and mild hyperreflexia (3 + ) but


there was no clonus or spasticity, and Babinski’s sign was negative. The weight was 43.9 kg (+ 1 SD), height was 151 cm (+ 1 SD), and head circumference 52.5 cm (− 0.8 SD). Magnetic


resonance imaging (MRI) of the brain at the same age showed agenesis of corpus callosum and multiple cortical heterotopias (See Fig. 1). PATIENT 2 This girl is the older sister to patient 1.


She was born at term after a normal gestation. Birth weight was 3330 g (− 0.5 SD), length was 50 cm (± 0 SD), and head circumference was 34 cm (− 1 SD). The APGAR score was 10–10–10 and the


perinatal period was uncomplicated. The psychomotor development was delayed and she started to say single words and to walk unsupported at 2 years of age. Psychological testing at 7 years


of age revealed a mild learning disability and the girl has attended special school. During childhood, she was healthy except for day and nighttime urinary incontinence, which disappeared


during adolescence. At 7 years of age, weight was 22.9 kg (± 0 SD), height was 122.3 cm (± 0 SD), and the head circumference was 50 cm (− 1 SD). She was first investigated by us at 25 years


of age as a consequence of the findings observed in her brother (patient 1). She was at that time generally healthy. Clinical examination was normal except for a mild action tremor and mild


hyperreflexia (3 + ) but there was no clonus or spasticity, and Babinski’s sign was negative. MRI of the brain and ophthalmological investigations were normal. DETECTION OF GSH IN URINE


Amino acids in urine were analyzed by cation-exchange chromatography followed by ninhydrin derivatization and spectrophotometric detection on an AminoTac JLC-500/V analyzer (JEOL, Croissy


Sur Seine, France) essentially as described [16]. Hydrolysis on vapor-phase was carried out as described [17] by incubating a urine sample with 6 N HCl for 24 h at 110 °C on a Pico-Tag


workstation (Waters, Milford, MA, USA). DETERMINATION OF Γ-GT ACTIVITY IN SERUM The activity of γ-GT in serum was analyzed spectrophotometrically on a COBAS c 501 autoanalyzer (Roche


Diagnostics Scandinavia AB, Solna, Sweden) following the manufacturer’s instructions. WHOLE-GENOME SEQUENCING AND SANGER VERIFICATION DNA obtained from blood was extracted using QIAamp DNA


Blood Mini Kit (Qiagen Benelux BV, Venlo, The Netherlands). One microgram of purified DNA was sent for sequencing at the Clinical Genomics facility at the Science for Life Laboratory, Solna,


Sweden, for whole-genome sequencing (WGS) on the Illumina Xten at 30 × coverage. Sequencing returned ~ 139 Gb, corresponding to a 44.78 × coverage before quality trimming. The sample was


then trimmed, mapped, and variant called using CLC Biomedical Server (Qiagen Aarhus, Aarhus, Denmark) with a workflow developed at the Clinical Genomics Gothenburg facility. The data set was


trimmed (limit 0.02, minimum length 30, max number of ambiguous bases 2) and then mapped against the hg19 reference genome (98.86% total reads mapped, 91.87% total reads in pairs). After


mapping, indels were called (_p_-value 0.001, max mismatches 3, minimum reads 2) and the mapping was locally realigned in three passes using the indel data. Variants were generated using the


CLC Fixed Ploidy variant caller (minimum coverage 7, minimum count 2, minimum frequency 15%) and the results filtered against RefSeq HG19 coding sequences. Variants were analyzed with


Ingenuity Variant Analysis software (Qiagen Aarhus, Aarhus, Denmark) and Integrative Genomics Viewer (IGV) visualization tool [18]. The deletion identified by WGS was verified by Sanger


sequencing using primers amplifying the genomic region harboring the deletion in chromosome 22 (including parts of _GGT1_). Sequencing analysis was performed using an ABI PRISM 3130XL


Genetic Analyzer and the BigDye Terminator v.1.1 Cycle Sequencing Kit (Applied Biosystems, ThermoFisher Scientific, Waltham, MA, USA). Primer sequences and PCR conditions are available upon


request. The deletion reported in this manuscript has been submitted to the Leiden Open Variation Database (https://databases.lovd.nl/shared/variants/0000236419) with ID: GGT1_000001.


RESULTS The analysis of amino acids in urine revealed the presence of three peaks of unclear origin with retention times close to aspartate, glycine, and citrulline respectively (see peaks


marked with asterisks in Fig. 2a). This pattern was essentially identical in both patients. On close observation, the first two peaks had retention times consistent with reduced and oxidized


GSH, respectively (Fig. 2b), whereas the peak close to citrulline could correspond to a thio-compound previously described in a patient with glutathionuria [11]. Hydrolysis with 6 N HCl


(Fig. 2c) resulted in the disappearance of all three peaks and a concomitant increase of glutamate, glycine, and cystine. It is well described that hydrolysis in 6 N HCl completely


transforms glutamine to glutamate (as well as asparagine to aspartate), and that cysteine is oxidized to cystine in non-reducing conditions. The inferred increases of glutamate and cysteine


(in the form of cystine) after hydrolysis are nearly equimolar (~ 1 mmol/l; we could not quantify glycine in the pre-hydrolysis sample due to the interference of oxidized GSH). Taken


together, we conclude that both the original pattern of amino acids and the results of the hydrolysis are consistent with glutathionuria. This diagnosis was further supported by analysis of


γ-GT activity in serum, which was under the limit of quantification of the technique in both affected siblings (< 0.05 µkat/l, reference ranges: < 0.6 for patient 1 and 0.15–0.75 for


patient 2). γ-GT activity of both parents laid within the normal range for their respective ages and genders (mother: 0.18 µkat/l, reference range: 0.15–1.2; father: 0.28 µkat/l, reference


range: 0.20–1.9). In order to confirm the diagnosis we took a genetic approach. As the genetic cause of glutathionuria was not known, we created an in silico panel containing all expressed


genes in the human γ-GT gene family as defined by Heisterkamp et al. [12], namely _GGT1_, _GGT2_, _GGT5_,_ GGT6_, _GGT7_, _GGTLC1_, _GGTLC2_, and _GGTLC3_, and used WGS as the sequencing


platform for patient 1. Initial analysis did not detect any single nucleotide variants nor small insertions/deletions of potential pathogenic nature in any of the genes included in the


panel. However, close inspection using IGV browser indicated the presence of a large homozygous deletion in _GGT1_, which included the first coding exon of all isoforms (Fig. 3a). Analysis


of the soft-clipped ends (that is, fragments of reads not mapped to the reference sequence) of the reads that cover the junction revealed the exact location of both breakpoints at positions


Chr22:24,992,587 (centromeric) and Chr22:25,009,579 (telomeric), respectively (Fig. 3b). In addition, the alignment of both sets of reads revealed the presence of a 13 bp insertion identical


to two sequences, each one in the vicinity of each breakpoint (Fig. 3c). As opposed to the centromeric breakpoint, a number of reads at the telomeric breakpoint align to the reference


sequence past the breakpoint (see Fig. 3c, central panel). Interestingly, all those reads contain mismatches that can be traced to pseudogenes _GGT3P_ and _GGT4P_. Consequently, we conclude


that those reads are misaligned to _GGT1_. _GGT1_-specific primers flanking the deletion junction gave a PCR product with the expected size (primers Fw and Rev2 in Fig. 4a). Sequencing of


the PCR product confirmed the WGS findings (Fig. 3c, bottom panel). A second set of primers was designed to give a PCR product only in the absence of the deletion (primers Fw and Rev1 in


Fig. 4a). DNA from both affected siblings produced a PCR product from the first primer pair but not from the second, whereas DNA from the parents produced PCR products from both primer


pairs, as expected for heterozygotes for the deletion. DNA from a control sample produced a PCR product only from the second primer set (Fig. 4a). The healthy brother showed a pattern


consistent with heterozygosity for the deletion (data not shown). In conclusion, WGS data and Sanger sequencing indicate the presence of a homozygous 16,993 bp deletion combined to a 13 bp


insertion in _GGT1_ that removes the first coding exon and several non-coding exons of all isoforms of _GGT1_. DISCUSSION Despite being a condition already described in the early 70 s, only


a few patients with glutathionuria have been reported so far. In addition to this, the fact that some of these patients were detected by screening for amino acid defects in cohorts of


mentally retarded individuals or in infants (1 respective 3 in Table 1), that one of them is asymptomatic (3), and that one (4) was diagnosed with a second condition that could account for


her clinical picture, raises the question of ascertainment bias being coupled to this condition. The two patients reported here were diagnosed in the process of investigating the cause for


their moderate mental retardation, which happens to be the predominant clinical feature in all but one of the patients reported, a condition that perhaps is not always investigated with the


diagnostic tools necessary to establish the diagnosis of γ-GT deficiency. Identification of more cases will help to definitively establish γ-GT deficiency as the cause of the clinical


picture observed in these patients. One factor that could contribute to explain why the number of patients reported is so low is that GSH is not a metabolite commonly measured in clinical


laboratories, and that the identification of GSH with the amino acid analyzers based on ion-exchange chromatography and ninhydrin staining in use today is not straightforward. The presence


of extra peaks in the analysis of amino acids, especially in urine, is a common phenomenon and often corresponds to exogenous substances with no direct diagnostic significance. Moreover,


substance identification solely based on retention time can be difficult. Implementation of mass spectrometric methods for analysis of amino acids in clinical routine will provide a better


analytical platform for identification and quantification of amino acids, as well as di- and tripeptides with diagnostic value, such as GSH, selecting away other interfering substances [19].


Another key biochemical marker in the diagnosis of this condition is the activity of γ-GT in serum. However, γ-GT is mainly used as a marker of liver disease but is not usually included in


the screening of metabolic diseases. Glutathionuria has also proved elusive regarding its genetic cause. The presence of a number of genes and pseudogenes sharing high level of homology with


_GGT1_ (see Supplementary Figure 1) and the fact that some regions in _GGT1_ have low complexity have probably contributed to this. Moreover, large deletions are not easy to detect with


conventional sequencing methods. It will be very interesting to find out whether large deletions in _GGT1_ are a common cause for γ-GT deficiency. It is important to point out that WGS


provided all data needed to detect and characterize the reported indel to the nucleotide level, and by doing so it saved considerable time and resources that would have been needed had other


“less expensive” sequencing techniques been used in the genetic investigation. Human _GGT1_ is mostly expressed in kidney and small intestine. Compared with these, the level of expression


in brain is low and yet the main affected organ in all glutathionuria patients reported is the central nervous system. Attempts to address this apparent discrepancy with mice models of γ-GT


deficiency have not entirely succeeded [20,21,22,23]. These mice present a severe phenotype with dwarfism, cataracts, infertility, and early death as main symptoms. In one report, agitation


and tremor after stimulation was observed, although anatomic and histologic examination of the brains did not show any abnormality [21]. Another report suggested that the paucity of symptoms


related to the central nervous system in these mice might be explained by their shortened lifespan [23]. Two hypotheses as to the susceptibility of the nervous tissue to alterations in GSH


homeostasis have been proposed, namely its role as antioxidant and the possibility of GSH acting as neurotransmitter, either as such or as a source of glutamate, glycine, and cysteine, all


three neuroactive substances ([3] and references therein). MRI of the brain of patient 1 in our report has shown clear abnormalities, whereas MRI of patient 2 was normal. As no information


of this kind is available from any of the other patients reported in the literature, it will be of great relevance to collect MRI data from other patients to determine whether the


alterations found in patient 1 are a hallmark of the disease. Nucleotide resolution at the deletion junction allows us to speculate about the mechanism causing the deletion reported. Both


breakpoints are located on Alu elements: AluSc at the centromeric end and AluSx at the telomeric end (Fig. 4b). Alu–Alu-mediated recombination is a well-known cause for genomic


rearrangements. It was initially attributed to unequal non-allelic homologous recombination (NAHR), but the general consensus nowadays is that the degree of identity shared between Alu


elements is not high enough to support NAHR. Alternatively, microhomology-mediated DNA replication-based mechanisms have been proposed ([24] and references therein). Moreover, alignment of


both Alu sequences close to the breakpoints (Fig. 4b, central panel) reveals the presence of an area which is highly homologous to the Alu-DEIN consensus sequence, a recombinogenic hotspot


[25]. Analysis of the junction also revealed the presence of a 13 bp insertion, identical to two segments of DNA, one on each Alu element, which happens to be part of the Alu-DEIN sequence


(Fig. 4b, lower panel). Insertion of short templates originating from areas flanking copy number variation (CNV) junctions has been reported to be as frequent as 35% of simple CNV junctions


and proposed to represent short-distance template switches due to misalignment or replication slippage within the same replication fork [26]. Based on all this, we propose that the deletion


presented here is caused by a two step mechanism involving replication slippage, causing the 13 bp insertion, and microhomology-mediated, replication-based template switching between Alu


elements, causing the 14.9 kb deletion. We find it impossible to define the order in which the two events took place, nor which of the two possible regions was the origin of the insertion.


Different possibilities, all based on microhomologies ranging from 1 to 4 bp, are presented in Supplementary Figure 2. Although all of them are in principle possible, we would like to


suggest that the Alu-DEIN sequence present in both Alu elements has a crucial role in bringing both Alu elements in close proximity, thus favoring recombination in that particular region.


That would be in consonance with the growing concept that genomic architecture has an important role in guiding recombination events [27]. It is even tempting to speculate that a transient


structure between both replication forks interacting at the Alu-DEIN sequence facilitates backward replication slippage at precisely that region (Supplemetary Fig. 2, bottom panel). In


conclusion, we present two siblings with glutathionuria caused by a large deletion in _GGT1_. This is, to our knowledge, the first report linking a genetic variant to glutathionuria. The


heterozygous nature of the healthy parents and the healthy brother reaffirms the autosomal recessive inheritance pattern of this condition. The difficulty to identify GSH in urine with


conventional amino acid analyzers, the presence of multiple genes with partial homology with _GGT1_, and a diffuse clinical picture have possibly hindered the diagnosis of this disease in


the past. Extra care in the interpretation of amino acid profiles, hydrolysis of samples presenting extra peaks, or better still, mass spectrometric analysis of amino acids in clinical


routine, inclusion of serum γ-GT activity in the screening of metabolic diseases, and the use of WGS as first line of genetic investigation will significantly increase the chances of


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2014;28:2394–406. Article  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Donald Runsteen for excellent technical assistance in the analysis of urine amino acids. FUNDING


This work was partially financed with Laboratoriemedicin Research and Development funds, Sahlgrenska University Hospital, Gothenburg, Sweden. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *


Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden Niklas Darin * Department of Clinical Chemistry, Sahlgrenska


University Hospital, Gothenburg, Sweden Karin Leckström, Julia Lindgren, Gabriella Almén & Jorge Asin-Cayuela * Department of Laboratory Medicine, Sahlgrenska University Hospital,


Gothenburg, Sweden Per Sikora * Department of Clinical Genomics, Gothenburg Science for Life Laboratories, Gothenburg, Sweden Per Sikora Authors * Niklas Darin View author publications You


can also search for this author inPubMed Google Scholar * Karin Leckström View author publications You can also search for this author inPubMed Google Scholar * Per Sikora View author


publications You can also search for this author inPubMed Google Scholar * Julia Lindgren View author publications You can also search for this author inPubMed Google Scholar * Gabriella


Almén View author publications You can also search for this author inPubMed Google Scholar * Jorge Asin-Cayuela View author publications You can also search for this author inPubMed Google


Scholar CORRESPONDING AUTHOR Correspondence to Jorge Asin-Cayuela. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ELECTRONIC


SUPPLEMENTARY MATERIAL SUPPLEMENTARY FIGURE 1 SUPPLEMENTARY FIGURE 2 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Darin, N., Leckström, K., Sikora, P.


_et al._ γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in _GGT1_. _Eur J Hum Genet_ 26, 808–817 (2018). https://doi.org/10.1038/s41431-018-0122-6


Download citation * Received: 15 September 2017 * Revised: 21 December 2017 * Accepted: 01 February 2018 * Published: 26 February 2018 * Issue Date: June 2018 * DOI:


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