Identification of a novel mutation of Alpha-L-iduronidase gene in Tunisian families

doi:10.21203/rs.3.rs-4351559/v1

Background: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by α-L-iduronidase (IDUA) deficiency. MPS I is a severe condition with a heterogeneous clinical spectrum including progressive visceral, bone and, in severe forms, neurological damage. The aim of this study was the detection of a novel mutation and a mutation that has been already described in the IDUAgene from four MPS I patients with various clinical phenotypes (severe; 2 cases, intermediate 1 case and mild; 1 case).

Patients and methods: Biological and molecular studies were carried out on 4 patients from 3 distinct families, each from a consanguineous marriage and originating from different regions of Tunisia: Mahres (Sax), Skhira (Sfax) and Kairouan. Indeed, bioinformatics software were used to predict the potential functional impact of the identified mutations on IDUA protein.

Results: Two IDUA mutations were detected: one is a p.His356_Gln362del mutation, a novel mutation found in two patients with a severe phenotype. The other mutation p.P533R that produces an intermediate and a mild phenotype was found in two patients.

Crystallographic analysis of the IDUA protein revealed that an amino acid sequence spanning from His 356 to Gln 362 forms an essential bend involved in substrate binding. Indeed, the new mutation results in a deletion of seven amino acids (His356_Gln362del) of this elbow, resulting in undectable enzymatic activity. This observation was confirmed in patient P3, who died at the age of 6 years. The p.P533R mutation involves the modification of a proline amino acid with an arginine in the IDUA protein. This substitution results in the introduction of a bulkier amino acid, requiring more space in the contact region between the β-sheet structure and the substrate-bound helix. It is likely that this leads to a decrease in the affinity between the IDUA protein and its substrate.

Conclusion: Our study on the genetic profile of MPSI has provided more information into the disease, particularly through the identification of a novel small deletion (His356_Gln362del) and the identification of the most frequently encountered in Tunisian population p.P533R.

Mucopolysaccharidosis type I

IDUA gene

mutations

enzymatic activity

Tunisian patients

Mucopolysaccharidosis type I (MPS I) is a hereditary lysosomal storage disorder caused by a deficiency in the enzyme Alpha-L-iduronidase inherited through autosomal recessive pattern. This enzyme plays a crucial role in breaking down dermatan and heparan sulfates. Insufficient IDUA leads to the progressive buildup of undegraded mucopolysaccharides, resulting in distinct clinical presentations [1].

The IDUA gene resides on chromosome 4p16.3 and comprises 14 exons covering a span of 19 kb. Its transcription yields a 2.3 kb cDNA sequence, encoding a protein of 653 amino acids [2,3]. The Human Gene Mutation Database documents over 300 mutations and 40 polymorphisms associated with this gene (http://www.hgmd.org).

In past studies, mutations including missense and large deletions have been detected in patients exhibiting the severe phenotype. Additionally, other types of mutations such as nonsense, insertion-deletion, and splice site variants have been observed in individuals with both severe and mild phenotypes [4].

In Tunisia, consanguineous marriages, particularly between first cousins, predominate, constituting an estimated incidence of approximately 32%. Moreover, the Tunisian population exhibits a genetically heterogeneous profile, attributed to historical dynamics of invasions and migrations. Consequently, the systematic screening of IDUA mutations in MPS I patients is imperative within the Tunisian context. This approach is crucial for the precise identification of country-specific mutations, enabling the detection of heterozygotes, and facilitating prenatal diagnostic interventions [5]. The aim of the present study was to identify the genetic lesions in the IDUA gene. Indeed, bioinformatics tools was used to e better understand the clinical manifestation associated with this disease

Patients

The study included four patients (1, 2, 3 and 4) from three unrelated families (F1, F2, F3) from Mahres, Sfax, Skhira, Sfax and Kairouan respectively.

The patients were evaluated through a series of assessments, including detailed medical history, physical examination, routine hematological and biochemical tests and measurement of leukocyte IDUA activity. Subsequently, genetic testing was conducted to explore potential pathogenic mutations associated with MPS. Family histories and main clinical data are reported in Table 1.

The Ethics Committee of the Farhat Hached Hospital (Sousse, Tunisia) approved this study and, prior to collecting blood samples, the families supplied informed consent. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and approved by the Ethics Committees of the respective Tunisian hospitals

Patient of family 1

Patient 1, aged 5, was born from a consanguineous union at the 4th degree (Fig. 1). Since his birth in 2019, this patient has been under medical supervision due to a complex malformation syndrome. Investigations included a karyotype analysis and molecular assessment of exon 11 of the fibroblast-growth factor receptor 3 (FGFR 3) gene, prompted by suspicion of achondroplasia. Throughout 2019, the patient presented multiple clinical concerns, including bilateral corneal opacification, untreated spina bifida, kyphoscoliosis, suspected pancreatitis, umbilical hernia, bronchiolitis, and prolonged febrile episodes.

In February 2021, hospital admission was necessitated by abdominal distention. Given the constellation of symptoms, encompassing notable facial dysmorphia, kyphoscoliosis, recurrent otolaryngology infections, umbilical hernia, and developmental delay, a diagnosis of MPS I with an intermediate phenotype was contemplated.

Patient of family 2

Patient 2, aged 5, was born from a consanguineous marriage at the 4th degree (Fig. 1) and had a sibling who succumbed at 6 months old due to congenital heart disease. Since his birth, Patient 2 has been hospitalized due to a maternal-fetal infection and experienced severe bronchiolitis at 3 months of age. In 2019, the patient presented with abdominal distention and respiratory distress. Abdominal ultrasound revealed hepatosplenomegaly, calcific microstones in the right middle region, and mild bilateral pyelectasis.

Further investigations included cerebral magnetic resonance imaging (MRI) focusing on the hypothalamic-pituitary (HH) axis, revealing abnormalities in the white matter, micro-cavities, and enlarged Virchow-Robin spaces. Additionally, distinctive features such as a flared appearance of the sellaturcica, odontoid hypoplasia, and thickening of the transverse ligament were indicative of mucopolysaccharidosis. Ear, nose, and throat examination unveiled mixed hearing loss in the right ear, while ophthalmological assessment identified epithelial and stromal corneal dystrophy. Other notable clinical features included coarse facial features, hepatosplenomegaly, and an umbilical hernia. Based on this characteristic clinical profile, suspicion arose regarding MPS I with a mild phenotype in Patient 2.

Patients of family 3

Patients 3 and 4, siblings born from a consanguineous union at the 4th degree, both passed away toward the end of 2018 (Fig. 1). The eldest sibling (Patient 3) succumbed at the age of 6, displaying symptoms suggestive of MPS I. Clinical manifestations emerged at 1 year of age, characterized by facial dysmorphia featuring coarse features, thickened skin, macroglossia, and hepatosplenomegaly. Subsequently, the patient developed gingival hypertrophy, dental spacing, corneal opacities, joint stiffness, and lumbar dorsal kyphosis.

The younger sibling, Patient 4, a male, passed away at the age of 5, one-year junior to his sister. His clinical presentation mirrored that of his elder sister (Patient 3), encompassing similar symptoms and signs.

Biological diagnosis

This biological study was carried out in the biochemistry laboratory at Farhat Hached Hospital, Sousse, Tunisia.

Measurement of α-L-IDURONIDASE activity

Leucocyte suspension was added to 20µl of substrate "4 methylumbelliferyl- α-L-iduronide", 20µl of 0.2M formate buffer and 5µl of distilled water. The reaction mixture and a blank tube were incubated at 37°C for 2 hours. Finally, the reaction was stopped by adding 1.5ml of 0.5M bicarbonate-carbonate buffer at pH 10.6. An immediate reading was taken at a wavelength of 660 nm by comparison with a crystallized phenol standard.

IDUA molecular analysis

Genomic DNA was extracted from peripheral blood leukocytes. Each of 14 exons and flanking intron-exon junctions was amplified as described previously[6].

Clinical features and IDUA activity

The clinical features of each patient and leukocyte IDUA activities are presented in Table 2. IDUA activities ranged from 0 to 0.39µKat/kg of protein. (Normal values: 1.7 --3.5 µKat/kg of protein).

IDUA mutations analysis

We analyzed the IDUA gene of four MPS I patients from Tunisia. The affected probands in the three unrelated families proved the presence of two cases of Hurler phenotype, one case of Huler / Scheie phenotype and one case of Scheie phenotype.

We found one previously reported mutation: P533R (Fig. 2) and one novel mutation p.His356_Gln362del (Fig. 3). All mutations and polymorphisms were confirmed in the parental DNA. All MPS I patients from the three families were homozygous for the identified mutations (Fig .2 and 3).

Bioinformatics finding

p.P533R mutation

We have demonstrated that the p.P533R mutation is located in the beta sandwich domain at a bend very close to the helix involved in substrate binding (red helix) (Fig. 4a). In this mutation is due to a substitution of a small amino acid proline by another large charged amino acid, arginine.

In fact, proline is a neutral amino acid, but its cyclic ring in its side chain limits its flexibility. We observed that its position close to the helix involved in substrate binding requires precise folding so as not to disrupt this binding. Thus, the introduction of a larger amino acid like Arginine requires more space in the contact region between the beta-sheet structure and the substrate-bound helix, which could result in a probable decrease in the affinity between the protein and its substrate.

Furthermore, the mutation of the residue to Arginine induces flexibility and a high charge, which creates a steric conflict, as shown by the crystallographic analysis (Fig. 4b). This steric conflict manifests itself by repulsions with neighboring amino acids, in particular those of the helix involved in binding to the substrate. Therefore, it can be concluded that the p.P533R mutation affects both the stability and activity of the protein.

p.His356_Gln362del

Crystallographic analysis of the IDUA protein revealed that an amino acid sequence from His 356 to Gln 362 forms a crucial bend involved in substrate binding (Fig. 5). The sequence containing residues Glu182 and Glu299 forms the catalytic site of the protein, strictly necessary for its enzymatic activity. Consequently, the prediction of the involvement of this deletion of this seven amino acid bend (Fig. 5a) on the 3D structure and the superposition of the normal and mutant protein (Fig. 5b and 5c) by the swiss PDB viewer® software confirm that the two glutamic acid residues involved in this activity are eliminated, leading to a deformation of the IDUA protein (Fig. 6), the loss of the substrate binding site and, consequently, zero enzymatic activity.

Mucopolysaccharidosis type I (MPS I) affects between 0.69 and 1.66 newborns per 100,000 worldwide [7]. Its prevalence varies from one country to another, suggesting that the distribution of this disease is linked to geographical location and ethnic origin. It is estimated at 3.2/100,000 newborns in Saudi Arabia, 0.69/100,000 newborns in Germany and 1.33/100,000 newborns in Portugal [8].

In Tunisia, the incidence of all mucopolysaccharidoses has been estimated at 3.2 per 100,000 births and the consanguineous marriages account for 32% of marriages. This frequency may be as high as 60% in rural areas of the country. This prevalence is comparable to that of other Arab countries such as Sudan (52%) and Algeria (22.6%) [5].

In Tunisia, MPS I accounts for 15.07% of all MPS, with an estimated incidence of 1.91 cases per 100,000 newborns, which is the highest and associated with mucopolysaccharidosis type III (MPS III) [9].

The incidence of the mild form of MPS I (Scheie syndrome) varies from 1 in 115,000 to 500,000 live births, and that of the severe form (Hurler syndrome) from 1 in 100,000 [10].

Molecular studies of the IDUA gene have identified more than 300 different mutations, the most common of which are p.Q70X and p.W402X in the Caucasian population and p.P533R in the North African population [5]. More than 60 polymorphisms, some of which lead to a change in amino acids, have also been described in the literature.

In this study, all the patients examined were from consanguineous marriages, a result consistent with several previous studies on this condition. According to several studies, this behavior appears to be closely linked to the socio-economic and cultural status of populations.

This hereditary disease may be a social and economic concern, relatively more so in Tunisia due to the high prevalence of consanguineous marriages. The level of consanguinity is likely to be high given the lack of awareness and the attachment of individuals to their traditional cultural values. The high frequency of intermarriage between relatives with patients affected by autosomal recessive diseases was very important and would increase the incidence of certain lesions such as the p.P533R mutation in Tunisian and Moroccan MPS I patients, and consequently a close relationship could be established between consanguinity and certain genetic diseases.

Phenotypic expression of mucopolysaccharidosis type I

The clinical picture in MPS I is often heterogeneous. Clinical signs appear progressively with varying degrees of severity[10].

In our study, in the two patients 3 and 4 from the third family with Hurler syndrome, mental retardation, facial dysmorphia, corneal opacity, hepatosplenomegaly and skeletal deformity were constant features. Survival did not exceed 10 years. This clinical description observed in the two patients studied is consistent with the literature [11].

The intermediate form of the disease, or Hurler/Scheie syndrome, is characterized by mental retardation and variable survival, hepatomegaly, multiple dysostoses, and a slow course, although it may be beset at any time by complications (especially cardiac and/or respiratory) that are sometimes fatal [12]. All these clinical symptoms are observed in the patient 1, who stopped his studies in the first year because of mental retardation.

The attenuated form (Hurler/Scheie syndrome) is characterized by hepatosplenomegaly, multiple dysostosis, almost normal survival and no mental retardation [12]. This clinical picture was found in the patient 2, who continued to attend school almost normally until the present day.

Mutations identified

The missense mutation p.P533R

Patients 1 and 2 were homozygous for the p.P533R missense mutation. This lesion in exon 11 (CCG-CGG) leads to the substitution of a neutral amino acid (proline) by a basic amino acid (arginine) at position 533 of the IDUA protein. This hIDUA- p.P533R mutant protein has been shown to retain some residual catalytic activity when expressed in Chinese hamster ovary (CHO) cells [13]. The patient 1 presented the intermediate form of the disease (Hurler/Scheie) and the patient 2 presented the attenuated form (Scheie syndrome), both of which are associated with residual enzymatic activity.

Crystallographic study of the IDUA protein showed that the Pro533 residue is close to the helix involved in substrate binding. The introduction of a larger amino acid such as arginine (Arg) requires more space in the contact between beta sandwich and the helix involved in substrate binding, which probably results in a decrease in affinity between the protein and the substrate. In addition, the intoduction of this mutant residue (Arg) increases the flexibility and charge of the protein, leading to a steric hindrance reaction with neighbouring amino acids, especially those of the helix in contact, hence the repulsion between the mutant residue and the helix that binds the substrate. We can therefore deduce that this mutation affects the protein stability and activity of the IDUA protein.

The novel p.His356_Gln362del

The two brothers 3 and 4 were homozygous for the novel deletion; p.His356_Gln362del in exon 8, which results in the deletion of 21 nucleotides located at position g.1002362_1002382del of the cDNA, leading to the deletion of seven amino acids in the protein sequence composed of 653 amino acids. Crystallographic analysis of the IDUA protein revealed that an amino acid sequence from His 356 to Gln 362 forms a crucial bend involved in substrate binding. This sequence, comprising residues Gln 182 and Gln 188, constitutes the catalytic site of the protein and is therefore essential for its catalytic activity. Deletion of this sequence leads to loss of the substrate binding site, resulting in zero enzymatic activity. This lack of activity was observed in the two patients 3 and 4, who unfortunately died at the age of 6 and 5 respectively.

In the case where the family is not listed and the MPS I mutation is unknown, the strategy currently adapted in our laboratory is based on the search, in the first instance, for the p.P533R mutation most frequently identified in Tunisian MPS I patients [6]followed by complete sequencing of the gene if this mutation is absent [5]. The choice of this methodology is appropriate for our laboratory and for the molecular characteristics of our MPS I population.

The treatment of mucopolysaccharidosis type I (MPS I) is based mainly on two approaches: bone marrow transplantation and enzyme replacement therapy. However, it is important to note that these two therapeutic approaches cannot treat the neurological disorders associated with the disease [14]. In Tunisia, MPS I patients are generally hospitalized to treat complications such as umbilical hernias and skeletal deformities. None of the patients studied received one of the two treatments. Genetic analysis remains the main hope for families at risk. This analysis provides reliable genetic counselling and also enables prenatal diagnosis and in-depth family investigation. In our study, the 3rd family underwent prenatal diagnosis after the death of the two children 1 and 2. The prenatal diagnosis showed that the foetus was heterozygous for the p.His356_Gln362del mutation and had a similar profile to the parents.

Our study was guided firstly by clinical data, followed by quantitative and qualitative analysis of urinary GAGs. The diagnosis was then confirmed in all cases by determining the enzymatic activity of IDUA.

Molecular analysis of the IDUA gene was performed in all patients to identify the molecular lesion causing the disease. The combinations of the biological, clinical and genetic data lead to better understand the mechanism of the function of the IDUA protein and the relationship between its structure.

MPS I: Mucopolysaccharidosis type I; IDUA: alpha-L-iduronidase; DNA: deoxyribonucleic acid; MRI: cerebral magnetic resonance imaging; HH: hypothalamic-pituitary

Ethics approval and consent to participate

The families gave informed consent before with drawal of blood samples and written informed consent was obtained and signed by all MPS I and controls families, in addition the verbal consent was also obtained during consultation. The study was approved by the ethics committees for scientific research of the La Rabta Hospital Tunis, Tunisia; no reference number was issued. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 and approved by the Ethics Committees of the respective Tunisian hospitals.

Consent to publication

Written informed consent was obtained from the parents or legal guardians of the patients for their participation and publication of this work. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Availability of data and materials

The datasets analysed during the current study are available in the ensemble database (https://www.ensembl.org/index.html) under the rs ID number : rs121965021 (P533R)and they are also available from the corresponding author upon request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was not financially supported.

Authors’ Contributions

MR, LC, YA, FH, HB and CS carried out all the experiments, data analyses, MR and LC and SF: wrote the manuscript. YA: carried out bioinformatics analysis. TM, HB, HBA, and SF supported the analysis and interpretation of the data. LC: revised the manuscript. All authors participated in the writing of the manuscript and approved the final version.

Acknowledgements

We thank all clinicians for their fruitful participation in this work. We also thank all families with MPSI and all control families for participating in this study.

Authors' information

¹Research Laboratory of Human Genome and Multifactorial Diseases, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia. ² Biochemistry Laboratory (LR00SP03), Bechir Hamza Children’s Hospital, Tunis, Tunisia. ³University of Jendouba, Higher Institute of Applied Studies in Humanity Le Kef, Department of Educational Sciences, Kef, Tunisia. ⁴ Pediatrics department, La Rabta hospital. ⁵Laboratory of Biochemistry, Farhat Hached Hospital Sousse, Tunisia

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Table I: Clinical and phenotypic data on the patients studied

Families	1	2	3
Origin	Mahres, Sfax	Skhira, Sfax	Kairouan
Patients	1	2	3	4
Age	5 years	5 years	Died at the age of 6	Died at the age of 5
Age at onset of symptoms	3 years	3 years	1 year	1 year
Gender	male	male	female	male
Consanguinity	4th degree	4th degree	4th degree	4th degree
Mental retardation	+	-	++	++
Growth retardation	+	+	++	++
Facial dysmorphia	+	+	++	++
Corneal opacities	+	+	++	++
Skeletal deformity	+	-	++	++
Hepatosplenomegaly	+	+	++	++
Umbilical hernia	+	+
Phenotype	Intermediate	attenuated	Severe	Severe

(+) : present ; (-) : absent ; (++) : severe

Table II : Results of biological data from patients studied

Families

1

2

3

Origins

Mahres , Sfax

Skhira, Sfax

Kairouan

Patients

1

2

3

4

Urinary GAGs

CS++ HS++ DS++

Hexuronic acid values in mg of acid glucuroniques/g of creatinine

47

Indicator : 12,20

17

Indicator : 10,89

-

Protein concentration (g/l)

3,50

Indicator : 4.86

3,75

Indicator : 3.25

4,56

Indicator : 2,8

4,73

Indicator: 2,74

Enzymatic activity of Hex (µkat/kg)

414

Indicator: 338

250

Indicator : 260

694

Indicator : 574

669

Indicator: 542

Enzymatic act of IDUA (µkat/kg)

0,39

Indicator : 15,58

0,30

Indicator : 15

0

Indicator: 3,32

0

Indicator : 2,37

Usual values

Hexuronic acid values in mg of acids glucuroniques/g of creatinine: 4.6 - 13

(3 to 7 years)

Enzymatic act of Hex (µkat/kg): 244 - 730

Enzymatic act of IDUA (µkat/kg): 2,4 - 16

GAGs : glycosaminoglycans ; Act : activity; Hex : Hexosaminidases ; IDUA : alpha-L-iduronidase; CS: Chondroitin sulfate ; HS : heparan sulfate; DS: dermatan sulfate

No competing interests reported.

Identification of a novel mutation of Alpha-L-iduronidase gene in Tunisian families

Status:

Version 1

Abstract

Figures

Background

Patients and methods

Patients

Patient of family 1

Patient of family 2

Patients of family 3

Biological diagnosis

Measurement of α-L-IDURONIDASE activity

IDUA molecular analysis

Results

Clinical features and IDUA activity

IDUA mutations analysis

Bioinformatics finding

p.P533R mutation

p.His356_Gln362del

Discussion

Phenotypic expression of mucopolysaccharidosis type I

Mutations identified

The missense mutation p.P533R

The novel p.His356_Gln362del

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1