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: Muhammad Arshad Rafiq, Andreas W Kuss, Lucia Puettmann, Abdul Noor, Annapoorani Ramiah, Ghazanfar Ali, Hao Hu, Nadir Ali Kerio, Yong Xiang, Masoud Garshasbi, Muzammil Ahmad Khan, Gisele E Ishak, Rosanna Weksberg, Reinhard Ullmann, Andreas Tzschach, Kimia Kahrizi, Khalid Mahmood, Farooq Naeem, Muhammad Ayub, Kelley W Moremen, John B Vincent, Hans Hilger Ropers, Muhammad Ansar, Hossein Najmabadi
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 89 Issue 1 Pg. 176-82 (Jul 15 2011) ISSN: 1537-6605 [Electronic] United States
• PMID: 21763484 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• MANEA protein, human
• Mannosidases

Topics

• Adolescent
• Adult
• Amino Acid Sequence
• Asian People (genetics)
• Child
• Chromosomes, Human, Pair 9
• Consanguinity
• Female
• Genes, Recessive
• Genetic Linkage
• Genome-Wide Association Study (methods)
• Homozygote
• Humans
• Intellectual Disability (genetics)
• Iran
• Male
• Mannosidases (genetics, metabolism)
• Membrane Proteins (genetics, metabolism)
• Molecular Sequence Data
• Mutation, Missense
• Pakistan
• Pedigree
• Polymorphism, Single Nucleotide
• Protein Structure, Tertiary
• Young Adult