NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup

Abstract

BackgroundHereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative diseases. Thin Corpus Callosum (TCC) associated HSP is a distinguished subgroup of complex forms. Purines and pyrimidine, the basic DNA and RNA components, are regulating the cell metabolism, having roles in signal transduction, energy preservation and cellular repair. Genetic defects in nucleotide metabolism related genes have been only recently implicated in brain and neurodegenerative diseases’ pathogenesis.Case presentationWe present a consanguineous Qatari family with two brothers, 9 and 3 years, who displayed a characteristic phenotype of early onset and markedly-severe spasticity with tiptoe walking, delayed dysarthric speech, persistent truncal hypotonia, and multiple variable-sized areas of brownish skin discoloration appearing at different places on the body. A clinical diagnosis suggestive of complex hereditary spastic paraplegia (HSP) was set after the family had the second affected child. Whole genome sequencing identified a novel homozygous NT5C2 splice site mutation (NM_012229.4/NM_001134373.2: c.1159 + 1G > T) that recessively segregated in family members. Brain MRI revealed dysgenic and thin corpus callosum (TCC) with peri-trigonal white matter cystic changes in both affected boys, whereas a well-developed corpus callosum with normal white matter was shown in their apparently normal brother, who found to be a carrier for the mutant variant. This mutation led to skipping of exon 14 with removal of 58 amino acid residues at the C-terminal half. The aberrantly spliced NT5C2 showed substantial reduction in expression level in the in-vitro study, indicating marked instability of the mutant NT5C2 protein.ConclusionThe present report expands the phenotypic spectrum of SPG45 and confirms NT5C2-SPG45 as a member of the rare TCC SPG-subtypes. Homozygous alteration in NT5C2 seems essential to produce central white matter developmental defects. The study highlights the importance of cytosolic II 5’-nucleotidase (NT5C2) in maintaining the normal balance of purines’ pool in the brain, which seems to play a pivotal role in the normal development of central white matter structures.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0395-6) contains supplementary material, which is available to authorized users.

Novel homozygous missense mutation in NT5C2 underlying hereditary spastic paraplegia SPG45

“…NT5C2 has also been implicated in schizophrenia, leukemia, and hypertension (Aberg et al, ; Kelly et al, ; Meyer et al, ), but the loss‐of‐function (frameshift, nonsense, splice site) mutations identified by Novarino et al () establish this as the causative gene in SPG45. Underscoring this association, a further autosomal recessive splice site mutation in NT5C2 has also been reported in two more siblings with SPG45 (Elsaid et al, ).…”

“…Novarino et al () studied the family reported by Dursun et al () and eight individuals from four additional families with SPG45. Recently, Elsaid et al () reported two additional brothers of a consanguineous Qatari family harboring a novel homozygous NT5C2 splice site mutation. They were unique to all other patients reported so far with SPG45 in that they displayed persistent early truncal hypotonia, dysarthria, and variable‐sized patches of skin brownish discoloration that appeared at 6 years of age.…”

Exome Analysis Identified Novel Homozygous Splice Site Donor Alteration in NT5C2 Gene in a Saudi Family Associated With Spastic Diplegia Cerebral Palsy, Developmental Delay, and Intellectual Disability

“…Among all other patients reported so far with CP, they were unique in that they displayed persistent early in 2017, truncal hypotonia, dysarthria, and variable-sized patches of brownish skin staining at early stage of life (Elsaid et al, 2017). Straussberg describes the clinical, radiologic, and genetic findings in three affected members of the consanguineous family from Arab region CP belonging to that harbors a novel mutation in NT5C2 (c.1379T > C; p.Leu460Pro) (Elsaid et al, 2017). Moreover, recently exon rearrangement c.771 + 573_814-298del reported in the in NT5C2 loci in a family with a complex genetic hereditary spastic paraplegias (Darvish et al, 2017).…”

“…Recently Elsaid et al reported a consanguineous Qatari family having a novel homozygous c.1159 +1G > T in NT5C2 splice site mutation (NM_012229.4/ NM_001134373.2). Among all other patients reported so far with CP, they were unique in that they displayed persistent early in 2017, truncal hypotonia, dysarthria, and variable-sized patches of brownish skin staining at early stage of life (Elsaid et al, 2017). Straussberg describes the clinical, radiologic, and genetic findings in three affected members of the consanguineous family from Arab region CP belonging to that harbors a novel mutation in NT5C2 (c.1379T > C; p.Leu460Pro) (Elsaid et al, 2017).…”

“…The NT5C2 gene catalyzes the adenosine hydrolysis along with monophosphate and inosine monophosphate-releasing adenosine which play a key role in promoting myelin formation in the central nervous system. Adenosine prevents proliferation of oligodendrocyte progenitor cells, stimulates their differentiation into mature oligodendrocytes, and controls the communication of neurons and glial cells with the help of axons (Elsaid et al, 2017).…”