title: Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia.
abstract: Biallelic mutations of ALS2 cause a clinical spectrum of overlapping autosomal recessive neurodegenerative disorders: infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (ALS2). We report on eleven individuals affected with IAHSP from two consanguineous Pakistani families. A combination of linkage analysis with homozygosity mapping and targeted sequencing identified two novel ALS2 mutations, a c.194T > C (p.Phe65Ser) missense substitution located in the first RCC-like domain of ALS2/alsin and a c.2998delA (p.Ile1000*) nonsense mutation. This study of extended families including a total of eleven affected individuals suggests that a given ALS2 mutation may lead to a phenotype with remarkable intrafamilial clinical homogeneity.
authors.affiliation: a Institute of Biochemistry and Biotechnology (IBBt), UVAS , Lahore , Pakistan .
authors.forename: Shakeela
authors.initials: S
authors.lastname: Daud
authors.affiliation: b Institute of Human Genetics, University of Ulm , Ulm , Germany .|c International Graduate School in Molecular Medicine Ulm, University of Ulm , Ulm , Germany .|d Department of Biotechnology and Informatics , BUITEMS , Quetta , Pakistan .
authors.forename: Naseebullah
authors.initials: N
authors.lastname: Kakar
authors.affiliation: b Institute of Human Genetics, University of Ulm , Ulm , Germany .|e Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , Hamburg , Germany .
authors.forename: Ingrid
authors.initials: I
authors.lastname: Goebel
authors.affiliation: a Institute of Biochemistry and Biotechnology (IBBt), UVAS , Lahore , Pakistan .
authors.forename: Abu Saeed
authors.initials: AS
authors.lastname: Hashmi
authors.affiliation: a Institute of Biochemistry and Biotechnology (IBBt), UVAS , Lahore , Pakistan .|f Department of Microbiology , UVAS , Lahore , Pakistan .
authors.forename: Tahir
authors.initials: T
authors.lastname: Yaqub
authors.affiliation: g Cologne Center for Genomics (CCG), University of Cologne , Cologne , Germany .
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: g Cologne Center for Genomics (CCG), University of Cologne , Cologne , Germany .|h Center for Molecular Medicine Cologne (CMMC), University of Cologne , Cologne , Germany .|i Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne , Cologne , Germany .
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: j Clinical Genetics and Genomics, Royal Brompton Hospital , London , United Kingdom .|k National Heart and Lung Institute, Imperial College London , London , United Kingdom.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Morris-Rosendahl
authors.affiliation: a Institute of Biochemistry and Biotechnology (IBBt), UVAS , Lahore , Pakistan .
authors.forename: Muhammad
authors.initials: M
authors.lastname: Wasim
authors.affiliation: b Institute of Human Genetics, University of Ulm , Ulm , Germany .|e Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , Hamburg , Germany .
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Volk
authors.affiliation: b Institute of Human Genetics, University of Ulm , Ulm , Germany .|e Institute of Human Genetics, University Medical Center Hamburg-Eppendorf , Hamburg , Germany .
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.affiliation: d Department of Biotechnology and Informatics , BUITEMS , Quetta , Pakistan .
authors.forename: Jamil
authors.initials: J
authors.lastname: Ahmad
authors.affiliation: b Institute of Human Genetics, University of Ulm , Ulm , Germany .
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010154:Pakistan; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D055815:Young Adult
chemical_list: C438187:ALS2 protein, human; D020662:Guanine Nucleotide Exchange Factors
keywords: ALS2; alsin; amyotrophic lateral sclerosis; infantile-onset ascending hereditary spastic paralysis (IAHSP)