A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy
GEMIN5 is a multifunctional RNA-binding protein required for the assembly of survival motor neurons. Several bi-allelic truncating and missense variants in this gene are reported to cause a neurodevelopmental disorder characterized by cerebellar atrophy, intellectual disability (ID), and motor dysfu...
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MDPI AG
2023-03-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/3/707 |
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| author | Nazia Ibrahim Shagufta Naz Francesca Mattioli Nicolas Guex Saima Sharif Afia Iqbal Muhammad Ansar Alexandre Reymond |
| author_facet | Nazia Ibrahim Shagufta Naz Francesca Mattioli Nicolas Guex Saima Sharif Afia Iqbal Muhammad Ansar Alexandre Reymond |
| author_sort | Nazia Ibrahim |
| collection | DOAJ |
| description | GEMIN5 is a multifunctional RNA-binding protein required for the assembly of survival motor neurons. Several bi-allelic truncating and missense variants in this gene are reported to cause a neurodevelopmental disorder characterized by cerebellar atrophy, intellectual disability (ID), and motor dysfunction. Whole exome sequencing of a Pakistani consanguineous family with three brothers affected by ID, cerebral atrophy, mobility, and speech impairment revealed a novel homozygous 3bp-deletion NM_015465.5:c.3162_3164del that leads to the loss of NM_015465.5 (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) amino acid in one of the α-helixes of the tetratricopeptide repeats of GEMIN5. In silico 3D representations of the GEMIN5 dimerization domain show that this variant likely affects the orientation of the downstream sidechains out of the helix axis, which would affect the packing with neighboring helices. The phenotype of all affected siblings overlaps well with previously reported patients, suggesting that NM_015465.5: c.3162_3164del (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) is a novel <i>GEMIN5</i> pathogenic variant. Overall, our data expands the molecular and clinical phenotype of the recently described neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) syndrome. |
| first_indexed | 2024-03-11T06:29:55Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T06:29:55Z |
| publishDate | 2023-03-01 |
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| spelling | doaj.art-49b66bccba8b4df88118b5be518c21682023-11-17T11:18:20ZengMDPI AGGenes2073-44252023-03-0114370710.3390/genes14030707A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral AtrophyNazia Ibrahim0Shagufta Naz1Francesca Mattioli2Nicolas Guex3Saima Sharif4Afia Iqbal5Muhammad Ansar6Alexandre Reymond7Department of Zoology, Lahore College for Women University, Lahore 54000, PakistanDepartment of Zoology, Lahore College for Women University, Lahore 54000, PakistanCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, SwitzerlandBioinformatics Competence Center, University of Lausanne, 1015 Lausanne, SwitzerlandDepartment of Zoology, Lahore College for Women University, Lahore 54000, PakistanDepartment of Zoology, Lahore College for Women University, Lahore 54000, PakistanDepartment of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Aisle des Aveugles, 1004 Lausanne, SwitzerlandCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, SwitzerlandGEMIN5 is a multifunctional RNA-binding protein required for the assembly of survival motor neurons. Several bi-allelic truncating and missense variants in this gene are reported to cause a neurodevelopmental disorder characterized by cerebellar atrophy, intellectual disability (ID), and motor dysfunction. Whole exome sequencing of a Pakistani consanguineous family with three brothers affected by ID, cerebral atrophy, mobility, and speech impairment revealed a novel homozygous 3bp-deletion NM_015465.5:c.3162_3164del that leads to the loss of NM_015465.5 (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) amino acid in one of the α-helixes of the tetratricopeptide repeats of GEMIN5. In silico 3D representations of the GEMIN5 dimerization domain show that this variant likely affects the orientation of the downstream sidechains out of the helix axis, which would affect the packing with neighboring helices. The phenotype of all affected siblings overlaps well with previously reported patients, suggesting that NM_015465.5: c.3162_3164del (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) is a novel <i>GEMIN5</i> pathogenic variant. Overall, our data expands the molecular and clinical phenotype of the recently described neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) syndrome.https://www.mdpi.com/2073-4425/14/3/707TPR domainneurodevelopmental disordercerebral atrophyautosomal recessiveaspartic acid deletionconsanguinity |
| spellingShingle | Nazia Ibrahim Shagufta Naz Francesca Mattioli Nicolas Guex Saima Sharif Afia Iqbal Muhammad Ansar Alexandre Reymond A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy Genes TPR domain neurodevelopmental disorder cerebral atrophy autosomal recessive aspartic acid deletion consanguinity |
| title | A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy |
| title_full | A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy |
| title_fullStr | A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy |
| title_full_unstemmed | A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy |
| title_short | A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy |
| title_sort | biallelic truncating variant in the tpr domain of gemin5 associated with intellectual disability and cerebral atrophy |
| topic | TPR domain neurodevelopmental disorder cerebral atrophy autosomal recessive aspartic acid deletion consanguinity |
| url | https://www.mdpi.com/2073-4425/14/3/707 |
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