article 160 nature genetics • volume 29 • october 2001 The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis Yi Yang 1 , Afif Hentati 1 , Han-Xiang Deng 1 , Omar Dabbagh 2 , Toru Sasaki 1 , Makito Hirano 1 , Wu-Yen Hung 1 , Karim Ouahchi 1 , Jianhua Yan 1 , Anser C. Azim 1 , Natalie Cole 1 , Generoso Gascon 3 , Ayesha Yagmour 4 , Mongi Ben-Hamida 5 , Margaret Pericak-Vance 6 , Fayçal Hentati 5 & Teepu Siddique 1,7,8 Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlap- ping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degener- ation, as it may include several cell-signaling motifs with known functions, including three associated with gua- nine-nucleotide exchange factors for GTPases (GEFs). 1 Department of Neurology, Northwestern University Medical School, Chicago, Illinois, USA. 2 King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 3 Division of Pediatric Neurology, Brown University, Providence, Rhode Island, USA. 4 King Fahad Military Hospital, Jeddah, Saudi Arabia. 5 Institute of Neurology, Tunis, Tunisia. 6 Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA. 7 Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois, USA. 8 Northwestern University Institute of Neuroscience, Chicago, Illinois, USA. Correspondence should be addressed to T.S. (e-mail: t-siddique@northwestern.edu). Introduction Amyotrophic lateral sclerosis and primary lateral sclerosis (PLS) are closely related but clinically distinct neurodegenerative disor- ders 1–3 . Following the first description of these disorders, there was a period of diagnostic confusion, but the distinction between ALS and PLS has since become clear and diagnostic criteria have been established 1,2,4,5 . Both ALS and PLS are progressive paralytic disorders that result from dysfunction of the motor systems comprising the upper motor neurons (UMN) of the motor cortex and lower motor neurons (LMN) of the brainstem and the spinal cord. In PLS, the degeneration is confined to the UMN 1,6 , whereas in ALS, both sets of neurons are affected 5 . ALS is a more severe dis- ease, and its phenotype is influenced by the relative ratio of UMN to LMN involvement. The PLS phenotype 7–13 shows a slowly progressive spastic paresis involving all four extremities and mus- cles of facial expression, speech, swallowing, and sometimes eye movements and sphincter control. The diagnosis of PLS is essen- tially one of exclusion, as the UMN pathways can be involved in other disorders such as spondylitic myelopathy, vitamin B 12 defi- ciency, human T-lymphotropic virus 1 (HTLV-1) infection, ‘pure’ spastic paraparesis, multiple sclerosis, tumors, strokes or syringo- or bulbomyelia. The exact prevalence of PLS is not known 1 , but it is rarer than ALS and can be differentiated from it by the absence of denervation or reinnervation upon electromyo- graphic or muscle-biopsy examination 5 . PLS is insidious and may, at first, affect only the bulbar inner- vated muscles or cause spasticity in the lower extremities. It may be initially diagnosed as pseudobulbar palsy, spastic paraparesis, multiple sclerosis, early ALS 13 or other conditions. As symptoms of PLS evolve over time, early diagnostic confusion is common. The progression of symptoms over three to five years is therefore an essential consideration in the diagnosis of PLS 1,4 . It usually takes several years before the appearance of essential characteris- tics such as bulbospinal spasticity and continued absence of LMN involvement. Consistent with the anatomic pathology, positron emission tomography (PET) scanning and magnetic resonance imaging (MRI) show decreased 18-flurodeoxyglucose uptake and atrophy of the precentral gyrus, respectively 1 . Magnetic cortical stimulation shows prolonged central-motor conduction times 1,12,14 . Although PLS is a sporadic disorder of adult middle age 1 , it has been described in children (juvenile PLS, JPLS), both in iso- lated 15 as well as in familial circumstances 12,16 . To establish the diagnosis of JPLS, additional childhood-onset disorders such as the leukodystrophies, biotin-responsive encephalopathies and juvenile Leigh-like syndromes and other neurometabolic entities must be ruled out 12 . Because of the rigor of the diagnostic criteria and the rarity of familial disease, PLS has not been the subject of any intensive genetic investigation until this report, and no locus related to it has been mapped. The genetics of ALS is relatively better studied. In 10% of ALS cases, the disease is transmitted as a recessive or dominant trait. Four gene loci have been mapped to chromosomes 21q21, 2q33, 15q15–q21 and 9q34 (refs. 17–24). ALS linked to 21q is caused by mutations in SOD1 (refs. 5,6) that lead to a dominant gain of toxic function. The genes for other ALS loci have not been identified. We first linked the recessive form of juvenile ALS type 3 (ALS2, © 2001 Nature Publishing Group http://genetics.nature.com © 2001 Nature Publishing Group http://genetics.nature.com