Novel mutations of the SPG11 gene in hereditary spastic paraplegia with thin corpus callosum.
BACKGROUND
Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a clinically and genetically heterogeneous neurodegenerative disorder with genetic linkage to multi-loci. Recently pathogenic mutations in the KIAA1840 (now named SPG11) for SPG11, the major HSP-TCC locus, were identified; at least 42 different mutations have been detected.


OBJECTIVE
To study the clinical features and identify the SPG11 gene mutations in Chinese patients with HSP-TCC.


METHODS
Three kindreds with an autosomal recessive HSP-TCC and 5 cases with sporadic HSP-TCC in Chinese Hans were recruited. Detailed clinical history, neurological examination, MRI, electromyography, Mini Mental State Examination (MMSE), Spastic Paraplegia Rating Scale (SPRS) were presented. DNA samples of the 8 families were collected and mutation analysis of SPG11 gene was carried out by direct DNA sequencing.


RESULTS
Except for one patient whose age at onset was 3 years old, 10 patients manifested a relatively similar combination of adolescence-onset cognitive decline and spastic paraparesis with TCC on brain MRI. We identified 10 novel and one known mutations in our 8 HSP-TCC families, which were two nonsense mutations (c.5977C>T/p.Q1993X, c.4668T>A/p.Y1556X), three small deletions (c.6898_6899delCT/p.L2300AfsX2338, c.3719_3720delTA/p.I1240VfsX263, c.733_734delAT/p.M245VfsX246), four small insertions (c.7088_7089insATTA/p.Y2363X, c.2163_2164insT/p.I722YfsX731, c.7101_7102insT/p.K2368X, c.6790_6791insC/p.L2264PfsX2339), one deletion/insertion (c.654_655delinsG/p.S218RfsX219), and one splice mutation (c.7151+4_7151+7delAGTA/p.K2384fsX2386). Each family has a different mutation and all the mutations are predicted to cause early protein truncation.


CONCLUSIONS
This study widens the mutation spectrum of the SPG11 gene and the mutations in the SPG11 gene are also the major causative gene for HSP-TCC in the Chinese Hans. Screening of the whole gene is recommended in clinical practice.
Liao
Shu-sheng
SS
Department of Neurology, Xiangya Hospital, Central South University, #87 Xiangya Road, Changsha 410008, Hunan, China.
Shen
Lu
L
Du
Juan
J
Zhao
Guo-huan
GH
Wang
Xiao-yi
XY
Yang
Yi
Y
Xiao
Zi-quan
ZQ
Yuan
Yi
Y
Jiang
Hong
H
Li
Nan
N
Sun
He-dong
HD
Wang
Jun-ling
JL
Wang
Chun-yu
CY
Zhou
Ya-fang
YF
Mo
Xiao-yun
XY
Xia
Kun
K
Tang
Bei-sha
BS
D000328:Adult; D061085:Agenesis of Corpus Callosum; D044466:Asian People / Q000208:ethnology; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008609:Mental Status Schedule; D009154:Mutation / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult
D011506:Proteins; C520412:SPG11 protein, human