title: Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability.
abstract: We have used genome-wide genotyping to identify an overlapping homozygosity-by-descent locus on chromosome 9q34.3 (MRT15) in four consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability (NS-ARID) and one in which the patients show additional clinical features. Four of the families are from Pakistan, and one is from Iran. Using a combination of next-generation sequencing and Sanger sequencing, we have identified mutations in the gene MAN1B1, encoding a mannosyl oligosaccharide, alpha 1,2-mannosidase. In one Pakistani family, MR43, a homozygous nonsense mutation (RefSeq number NM_016219.3: c.1418G>A [p.Trp473*]), segregated with intellectual disability and additional dysmorphic features. We also identified the missense mutation c. 1189G>A (p.Glu397Lys; RefSeq number NM_016219.3), which segregates with NS-ARID in three families who come from the same village and probably have shared inheritance. In the Iranian family, the missense mutation c.1000C>T (p.Arg334Cys; RefSeq number NM_016219.3) also segregates with NS-ARID. Both missense mutations are at amino acid residues that are conserved across the animal kingdom, and they either reduce k(cat) by ∼1300-fold or disrupt stable protein expression in mammalian cells. MAN1B1 is one of the few NS-ARID genes with an elevated mutation frequency in patients with NS-ARID from different populations.
authors.affiliation: Molecular Neuropsychiatry and Development Lab, Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Muhammad Arshad
authors.initials: MA
authors.lastname: Rafiq
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
authors.forename: Lucia
authors.initials: L
authors.lastname: Puettmann
authors.forename: Abdul
authors.initials: A
authors.lastname: Noor
authors.forename: Annapoorani
authors.initials: A
authors.lastname: Ramiah
authors.forename: Ghazanfar
authors.initials: G
authors.lastname: Ali
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Nadir Ali
authors.initials: NA
authors.lastname: Kerio
authors.forename: Yong
authors.initials: Y
authors.lastname: Xiang
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
authors.forename: Muzammil Ahmad
authors.initials: MA
authors.lastname: Khan
authors.forename: Gisele E
authors.initials: GE
authors.lastname: Ishak
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.forename: Khalid
authors.initials: K
authors.lastname: Mahmood
authors.forename: Farooq
authors.initials: F
authors.lastname: Naeem
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
authors.forename: Kelley W
authors.initials: KW
authors.lastname: Moremen
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.forename: Hans Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D002648:Child; D002899:Chromosomes, Human, Pair 9; D003241:Consanguinity; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D055106:Genome-Wide Association Study / Q000379:methods; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007492:Iran; D008297:Male; D008361:Mannosidases / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010154:Pakistan; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C505100:MANEA protein, human; D008361:Mannosidases