Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan.
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.
Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.|Ecole Pratique des Hautes Etudes, EPHE, PSL université, Paris, France.|University of Khartoum, Khartoum, Sudan.
Liena E O
LEO
Elsayed
University of Khartoum, Khartoum, Sudan.
Inaam N
IN
Mohammed
University of Khartoum, Khartoum, Sudan.
Ahlam A A
AAA
Hamed
University of Khartoum, Khartoum, Sudan.
Maha A
MA
Elseed
Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
Adam
A
Johnson
Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.|Ecole Pratique des Hautes Etudes, EPHE, PSL université, Paris, France.
Mathilde
M
Mairey
Alnelain Medical Center, Khartoum, Sudan.|Sudan Medical Council, Neurology, Sudan.
Hassab Elrasoul S A
HESA
Mohamed
University of Khartoum, Khartoum, Sudan.|Sudan Medical Council, Neurology, Sudan.
Mohamed N
MN
Idris
Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Mustafa A M
MAM
Salih
University of Khartoum, Khartoum, Sudan.|Department of Neurology, Soba University Hospital, Khartoum, Sudan.
Sarah M
SM
El-Sadig
Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
Mahmoud E
http://orcid.org/0000-0001-9512-0184
ME
Koko
Department of Biochemistry, Faculty of Medicine, National University, Khartoum, Sudan.
Ashraf Y O
AYO
Mohamed
Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.|Ecole Pratique des Hautes Etudes, EPHE, PSL université, Paris, France.|Department of genetics, APHP Pitié-Salpêtrière Hospital, Paris, France.
Laure
L
Raymond
Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.|Ecole Pratique des Hautes Etudes, EPHE, PSL université, Paris, France.
Marie
M
Coutelier
Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.
Frédéric
F
Darios
Neelain University, Khartoum, Sudan.
Rayan A
RA
Siddig
University of Khartoum, Khartoum, Sudan.
Ahmed K M A
AKMA
Ahmed
University of Khartoum, Khartoum, Sudan.
Arwa M A
AMA
Babai
University of Khartoum, Khartoum, Sudan.
Hiba M O
HMO
Malik
University of Khartoum, Khartoum, Sudan.
Zulfa M B M
ZMBM
Omer
University of Khartoum, Khartoum, Sudan.
Eman O E
EOE
Mohamed
Department of Biochemistry, El Imam EL Mahdi University, Kosti, Sudan.
Hanan B
HB
Eltahir
Department of Radiology, Alamal National Hospital, Khartoum, Sudan.
Nasr Aldin A
NAA
Magboul
University of Khartoum, Khartoum, Sudan.
Elfatih E
EE
Bushara
Department of Radiology, Ribat University Hospital, Khartoum, Sudan.
Abdelrahman
A
Elnour
Department of Radiology, Alamal National Hospital, Khartoum, Sudan.
Salah M Abdel
SMA
Rahim
Antalya Medical Center, Khartoum, Sudan.
Abdelmoneim
A
Alattaya
University of Khartoum, Khartoum, Sudan.
Mustafa I
MI
Elbashir
Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
Muntaser E
ME
Ibrahim
Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.|Department of genetics, APHP Pitié-Salpêtrière Hospital, Paris, France.
Alexandra
A
Durr
Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
Anjon
A
Audhya
Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France. alexis.brice@upmc.fr.|Department of genetics, APHP Pitié-Salpêtrière Hospital, Paris, France. alexis.brice@upmc.fr.
Alexis
A
Brice
University of Khartoum, Khartoum, Sudan.|Sudan Medical Council, Neurology, Sudan.
Ammar E
AE
Ahmed
Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France. giovanni.stevanin@upmc.fr.|Ecole Pratique des Hautes Etudes, EPHE, PSL université, Paris, France. giovanni.stevanin@upmc.fr.|Department of genetics, APHP Pitié-Salpêtrière Hospital, Paris, France. giovanni.stevanin@upmc.fr.
Giovanni
G
Stevanin
D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D055815:Young Adult; D033921:Vesicular Transport Proteins
D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins; D011506:Proteins; C438187:ALS2 protein, human; C404403:SACS protein, human; C096163:TFG protein, human; D033921:Vesicular Transport Proteins