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Eur J Hum Genet. 2016 Jan;25(1):100-110. doi: 10.1038/ejhg.2016.108. Epub 2016 Sep 7.

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan.

Author information

1
Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.
2
Ecole Pratique des Hautes Etudes, EPHE, PSL université, Paris, France.
3
University of Khartoum, Khartoum, Sudan.
4
Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
5
Alnelain Medical Center, Khartoum, Sudan.
6
Sudan Medical Council, Neurology, Sudan.
7
Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
8
Department of Neurology, Soba University Hospital, Khartoum, Sudan.
9
Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
10
Department of Biochemistry, Faculty of Medicine, National University, Khartoum, Sudan.
11
APHP Pitié-Salpêtrière Hospital, Department of genetics, Paris, France.
12
Neelain University, Khartoum, Sudan.
13
Department of Biochemistry, El Imam EL Mahdi University, Kosti, Sudan.
14
Department of Radiology, Alamal National Hospital, Khartoum, Sudan.
15
Department of Radiology, Ribat University Hospital, Khartoum, Sudan.
16
Antalya Medical Center, Khartoum, Sudan.

Abstract

Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSP-related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C>T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C>T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.

PMID:
27601211
PMCID:
PMC5159756
DOI:
10.1038/ejhg.2016.108
[Indexed for MEDLINE]
Free PMC Article

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