PUBLICATION
Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay
- Authors
- Ansar, M., Riazuddin, S., Sarwar, M.T., Makrythanasis, P., Paracha, S.A., Iqbal, Z., Khan, J., Assir, M.Z., Hussain, M., Razzaq, A., Polla, D.L., Taj, A.S., Holmgren, A., Batool, N., Misceo, D., Iwaszkiewicz, J., de Brouwer, A.P.M., Guipponi, M., Hanquinet, S., Zoete, V., Santoni, F.A., Frengen, E., Ahmed, J., Riazuddin, S., van Bokhoven, H., Antonarakis, S.E.
- ID
- ZDB-PUB-170825-5
- Date
- 2017
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 20(7): 778-784 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Alleles
- Chromosome Mapping/methods
- Exome Sequencing
- Family
- Female
- Gene Frequency/genetics
- Genotype
- Homozygote
- Humans
- Intellectual Disability/genetics*
- Language Development Disorders/genetics
- Male
- Membrane Proteins/genetics*
- Membrane Proteins/physiology
- Microcephaly/genetics
- Motor Activity/genetics
- Mutation, Missense/genetics
- Nerve Tissue Proteins/genetics*
- Nerve Tissue Proteins/physiology
- Pakistan
- Pedigree
- Phenotype
- Sequence Analysis, Protein
- PubMed
- 28837161 Full text @ Genet. Med.
Citation
Ansar, M., Riazuddin, S., Sarwar, M.T., Makrythanasis, P., Paracha, S.A., Iqbal, Z., Khan, J., Assir, M.Z., Hussain, M., Razzaq, A., Polla, D.L., Taj, A.S., Holmgren, A., Batool, N., Misceo, D., Iwaszkiewicz, J., de Brouwer, A.P.M., Guipponi, M., Hanquinet, S., Zoete, V., Santoni, F.A., Frengen, E., Ahmed, J., Riazuddin, S., van Bokhoven, H., Antonarakis, S.E. (2017) Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay. Genetics in medicine : official journal of the American College of Medical Genetics. 20(7):778-784.
Abstract
PurposeTo elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.MethodsA combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software.ResultsAll five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.ConclusionLINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-of-function studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.GENETICS in MEDICINE advance online publication, 24 August 2017; doi:10.1038/gim.2017.113.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping