Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan
Liena Elsayed
(1, 2, 3)
,
Inaam Mohammed
(1)
,
Ahlam Hamed
(1)
,
Maha Elseed
(1)
,
Adam Johnson
(4)
,
Mathilde Mairey
(3, 2)
,
Hassab Elrasoul S A Mohamed
,
Mohamed Idris
(1)
,
Mustafa Salih
(5)
,
Sarah El-Sadig
(1)
,
Mahmoud Koko
(1)
,
Ashraf Mohamed
(1)
,
Laure Raymond
(2, 3, 6)
,
Marie Coutelier
(3, 2)
,
Frédéric Darios
(2)
,
Rayan Siddig
(7)
,
Ahmed Ahmed
(1)
,
Arwa Babai
(1)
,
Hiba Malik
(1)
,
Zulfa Omer
(1)
,
Eman Mohamed
(1)
,
Hanan Eltahir
,
Nasr Aldin A Magboul
,
Elfatih Bushara
(1)
,
Abdelrahman Elnour
,
Salah Rahim
(1)
,
Abdelmoneim Alattaya
,
Mustafa Elbashir
(1)
,
Muntaser Ibrahim
(1)
,
Alexandra Durr
(6, 2)
,
Anjon Audhya
,
Alexis Brice
(6, 2)
,
Ammar Ahmed
(1)
,
Giovanni Stevanin
(6, 2, 3)
Hassab Elrasoul S A Mohamed
- Fonction : Auteur
Mahmoud Koko
- Fonction : Auteur
- PersonId : 1365726
- ORCID : 0000-0001-9512-0184
Hanan Eltahir
- Fonction : Auteur
Nasr Aldin A Magboul
- Fonction : Auteur
Abdelrahman Elnour
- Fonction : Auteur
Abdelmoneim Alattaya
- Fonction : Auteur
Anjon Audhya
- Fonction : Auteur
Alexis Brice
- Fonction : Auteur
- PersonId : 1104774
- ORCID : 0000-0002-0941-3990
- IdRef : 050512935
Résumé
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.