Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family.
Front. Neurol.. 2020-10-29; 11:
DOI: 10.3389/fneur.2020.569996
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1. Front Neurol. 2020 Oct 29;11:569996. doi: 10.3389/fneur.2020.569996. eCollection
2020.
Novel Homozygous Missense Mutation in the ARG1 Gene in a Large Sudanese Family.
Elsayed LEO(1)(2)(3), Mohammed IN(1), Hamed AAA(1), Elseed MA(1), Salih MAM(4),
Yahia A(1)(3)(5)(6), Abubaker R(7), Koko M(8), Abd Allah ASI(1), Elbashir MI(1),
Ibrahim ME(7), Brice A(3)(9), Ahmed AE(1), Stevanin G(3)(6)(9).
Author information:
(1)Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
(2)College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh,
Saudi Arabia.
(3)Institut du Cerveau, INSERM, CNRS, Sorbonne Université, Paris, France.
(4)Division of Pediatric Neurology, Department of Pediatrics, College of
Medicine, King Saud University, Riyadh, Saudi Arabia.
(5)Department of Biochemistry, Faculty of Medicine, National University,
Khartoum, Sudan.
(6)Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris,
France.
(7)Department of Molecular Biology, Institute of Endemic Diseases, University of
Khartoum, Khartoum, Sudan.
(8)Department of Neurology and Epileptology, Hertie Institute for Clinical Brain
Research, Tuebingen, Germany.
(9)APHP, Pitié-Salpêtrière Hospital, Department of genetics, Paris, France.
Background: Arginases catalyze the last step in the urea cycle. Hyperargininemia,
a rare autosomal-recessive disorder of the urea cycle, presents after the first
year of age with regression of milestones and evolves gradually into progressive
spastic quadriplegia and cognitive dysfunction. Genetic studies reported various
mutations in the ARG1 gene that resulted in hyperargininemia due to a complete or
partial loss of arginase activity. Case Presentation: Five patients from an
extended highly consanguineous Sudanese family presented with regression of the
acquired milestones, spastic quadriplegia, and mental retardation. The disease
onset ranged from 1 to 3 years of age. Two patients had epileptic seizures and
one patient had stereotypic clapping. Genetic testing using whole-exome
sequencing, done for the patients and a healthy parent, confirmed the presence of
a homozygous novel missense variant in the ARG1 gene [GRCh37 (NM_001244438.1):
exon 4: g.131902487T>A, c.458T>A, p.(Val153Glu)]. The variant was predicted
pathogenic by five algorithms and affected a highly conserved amino acid located
in the protein domain ureohydrolase, arginase subgroup. Sanger sequencing of 13
sampled family members revealed complete co-segregation between the variant and
the disease distribution in the family in line with an autosomal-recessive mode
of inheritance. Biochemical analysis confirmed hyperargininemia in five patients.
Conclusion: This study reports the first Sudanese family with ARG1 mutation. The
reported variant is a loss-of-function missense mutation. Its pathogenicity is
strongly supported by the clinical phenotype, the computational functional impact
prediction, the complete co-segregation with the disease, and the biochemical
assessment.
Copyright © 2020 Elsayed, Mohammed, Hamed, Elseed, Salih, Yahia, Abubaker, Koko,
Abd Allah, Elbashir, Ibrahim, Brice, Ahmed and Stevanin.
DOI: 10.3389/fneur.2020.569996
PMCID: PMC7658625
PMID: 33193012