title: Infantile-onset ascending hereditary spastic paraplegia with bulbar involvement due to the novel ALS2 mutation c.2761C>T.
abstract: Recessive mutations in the alsin gene cause three clinically distinct motor neuron diseases: juvenile amyotrophic lateral sclerosis (ALS2), juvenile primary lateral sclerosis (JPLS) and infantile-onset ascending hereditary spastic paraplegia (IAHSP). A total of 23 different ALS2 mutations have been described for the three disorders so far. Most of these mutations result in a frameshift leading to a premature truncation of the alsin protein. We report the novel ALS2 truncating mutation c.2761C>T; p.R921X detected by homozygosity mapping and sequencing in two infants affected by IAHSP with bulbar involvement. The mutation c.2761C>T resides in the pleckstrin domain, a characteristic segment of guanine nucleotide exchange factors of the Rho GTPase family, which is involved in the overall neuronal development or maintenance. This study highlights the importance of using homozygosity mapping combined with candidate gene analysis to identify the underlying genetic defect as in this Saudi consanguineous family.
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Electronic address: smajid@kfshrc.edu.sa.
authors: Salma M
authors: SM
authors: Wakil
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Khushnooda
authors: K
authors: Ramzan
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Rula
authors: R
authors: Abuthuraya
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Samya
authors: S
authors: Hagos
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Haya
authors: H
authors: Al-Dossari
authors: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Rana
authors: R
authors: Al-Omar
authors: Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Hatem
authors: H
authors: Murad
authors: Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Aziza
authors: A
authors: Chedrawi
authors: Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Zuhair N
authors: ZN
authors: Al-Hassnan
authors: Krankenanstalt Rudolfstiftung, Vienna, Austria.
authors: Josef
authors: J
authors: Finsterer
authors: Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Saeed
authors: S
authors: Bohlega
mesh_terms: D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000502:physiology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D035781:Siblings; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: C438187:ALS2 protein, human; D020662:Guanine Nucleotide Exchange Factors
keywords: ALS2; Alsin-2 gene; Amyotrophic lateral sclerosis; DH/PH; Db1 and pleckstrin homology; GDP; GEF; GTP; GTPase; Hereditary spastic paraplegia; Homozygosity; IAHSP; JPLS; LMN; MORN; Motor neuron; Mutation; RCC1; ROH; Ras homologous member; Rho; UMN; VPS9; guanine exchange factor; guanosine diphosphate; guanosine triphosphatase NMD: nonsense-mediated mRNA decay; guanosinetriphosphatase; infantile-onset ascending hereditary spastic paraplegia; juvenile amyotrophic lateral sclerosis 2; juvenile primary lateral sclerosis; lower motor neurons; membrane occupation and recognition nexus; regions of homozygosity; regulator of chromatin condensation 1; upper motor neurons; vacuolar protein sorting 9