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

Liena E O Elsayed, Inaam N Mohammed, Ahlam A A Hamed, Maha A Elseed, Adam Johnson, Mathilde Mairey, Hassab Elrasoul S A Mohamed, Mohamed N Idris, Mustafa A M Salih, Sarah M El-sadig, Mahmoud E Koko, Ashraf Y O Mohamed, Laure Raymond, Marie Coutelier, Frédéric Darios, Rayan A Siddig, Ahmed K M A Ahmed, Arwa M A Babai, Hiba M O Malik, Zulfa M B M Omer, Eman O E Mohamed, Hanan B Eltahir, Nasr Aldin A Magboul, Elfatih E Bushara, Abdelrahman Elnour, Salah M Abdel Rahim, Abdelmoneim Alattaya, Mustafa I Elbashir, Muntaser E Ibrahim, Alexandra Durr, Anjon Audhya, Alexis Brice, Ammar E Ahmed, Giovanni Stevanin
Eur J Hum Genet. 2016-09-07; 25(1): 100-110
DOI: 10.1038/EJHG.2016.108

PubMed
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1. 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.

Elsayed LEO(1)(2)(3), Mohammed IN(3), Hamed AAA(3), Elseed MA(3), Johnson A(4),
Mairey M(1)(2), Mohamed HESA(5)(6), Idris MN(3)(6), Salih MAM(7), El-Sadig
SM(3)(8), Koko ME(9), Mohamed AYO(10), Raymond L(1)(2)(11), Coutelier M(1)(2),
Darios F(1), Siddig RA(12), Ahmed AKMA(3), Babai AMA(3), Malik HMO(3), Omer
ZMBM(3), Mohamed EOE(3), Eltahir HB(13), Magboul NAA(14), Bushara EE(3), Elnour
A(15), Rahim SMA(14), Alattaya A(16), Elbashir MI(3), Ibrahim ME(9), Durr
A(1)(11), Audhya A(4), Brice A(17)(18), Ahmed AE(3)(6), Stevanin G(19)(20)(21).

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)Department of genetics, APHP Pitié-Salpêtrière Hospital, 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.
(17)Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225,
Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.
.
(18)Department of genetics, APHP Pitié-Salpêtrière Hospital, Paris, France.
.
(19)Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225,
Sorbonne Universités, UPMC Université Paris VI UMR_S1127, Paris, France.
.
(20)Ecole Pratique des Hautes Etudes, EPHE, PSL université, Paris, France.
.
(21)Department of genetics, APHP Pitié-Salpêtrière Hospital, Paris, France.
.

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.

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

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