Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family

• Verfasst von: Rafiullah, Rafiullah [VerfasserIn]
• Verfasst von: Aslamkhan, Muhammad [VerfasserIn]
• Verfasst von: Paramasivam, Nagarajan [VerfasserIn]
• Verfasst von: Thiel, Christian [VerfasserIn]
• Verfasst von: Mustafa, Ghulam [VerfasserIn]
• Verfasst von: Wiemann, Stefan [VerfasserIn]
• Verfasst von: Schlesner, Matthias [VerfasserIn]
• Verfasst von: Wade, Rebecca C. [VerfasserIn]
• Verfasst von: Rappold, Gudrun [VerfasserIn]
• Verfasst von: Berkel, Simone [VerfasserIn]
• Titel: Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family
• Verf.angabe: Rafiullah Rafiullah, Muhammad Aslamkhan, Nagarajan Paramasivam, Christian Thiel, Ghulam Mustafa, Stefan Wiemann, Matthias Schlesner, Rebecca C Wade, Gudrun A Rappold, Simone Berkel
• Jahr: 2016
• Umfang: 7 S.
• Fussnoten: Published Online First 13 November 2015 ; Gesehen am 17.07.2020
• Titel Quelle: Enthalten in: Journal of medical genetics
• Ort Quelle: London : BMJ Publishing Group, 1964
• Jahr Quelle: 2016
• Band/Heft Quelle: 53(2016), 2, Seite 138-144
• ISSN Quelle: 1468-6244
• DOI: doi:10.1136/jmedgenet-2015-103179
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Epilepsy and seizures
• Sach-SW: Genetics
• Sach-SW: Neurosciences
• Sach-SW: Psychotic disorders (incl schizophrenia)
• K10plus-PPN: 172507740X

Abstract

Background Intellectual disability (ID) is a neurodevelopmental disorder affecting 1%-3% of the population worldwide. It is characterised by high phenotypic and genetic heterogeneity and in most cases the underlying cause of the disorder is unknown. In our study we investigated a large consanguineous family from Baluchistan, Pakistan, comprising seven affected individuals with a severe form of autosomal recessive ID (ARID) and epilepsy, to elucidate a putative genetic cause. - Methods and results Whole exome sequencing (WES) of a trio, including a child with ID and epilepsy and its healthy parents that were part of this large family, revealed a homozygous missense variant p.R53Q in the lectin mannose-binding 2-like (LMAN2L) gene. This homozygous variant was co-segregating in the family with the phenotype of severe ID and infantile epilepsy; unaffected family members were heterozygous variant carriers. The variant was predicted to be pathogenic by five different in silico programmes and further three-dimensional structure modelling of the protein suggests that variant p.R53Q may impair protein-protein interaction. LMAN2L (OMIM: 609552) encodes for the lectin, mannose-binding 2-like protein which is a cargo receptor in the endoplasmic reticulum important for glycoprotein transport. Genome-wide association studies have identified an association of LMAN2L to different neuropsychiatric disorders. - Conclusion This is the first report linking LMAN2L to a phenotype of severe ARID and seizures, indicating that the deleterious homozygous p.R53Q variant very likely causes the disorder.