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Truncating mutation in intracellular phospholipase A₁ gene (DDHD2) in hereditary spastic paraplegia with intellectual disability (SPG54).

Alrayes N, Mohamoud HS, Jelani M, Ahmad S, Vadgama N, Bakur K, Simpson M, Al-Aama JY, Nasir J - BMC Res Notes (2015)

Bottom Line: Hereditary spastic paraplegias (HSP), a group of genetically heterogeneous neurological disorders with more than 56 documented loci (SPG1-56), are described either as uncomplicated (or pure), or complicated where in addition to spasticity and weakness of lower extremeties, additional neurological symptoms are present, including dementia, loss of vision, epilepsy, mental retardation and ichthyosis.Exome sequencing identified a homozygous stop gain mutation (pR287X) in the phospholipase A1 gene DDHD2, in the affected individuals, resulting in a premature stop codon and a severely truncated protein lacking the SAM and DDHD domains crucial for phosphoinositide binding and phospholipase activity.This mutation adds to the knowledge of HSP, suggests a possible founder effect for the pR287X mutation, and adds to the list of genes involved in lipid metabolism with a role in HSP and other neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, 80205, Kingdom of Saudi Arabia. nuharayes@gmail.com.

ABSTRACT

Background: Hereditary spastic paraplegias (HSP), a group of genetically heterogeneous neurological disorders with more than 56 documented loci (SPG1-56), are described either as uncomplicated (or pure), or complicated where in addition to spasticity and weakness of lower extremeties, additional neurological symptoms are present, including dementia, loss of vision, epilepsy, mental retardation and ichthyosis. We identified a large consanguineous family of Indian descent with four affected members with childhood onset HSP (SPG54), presenting with upper and lower limb spasticity, mental retardation and agenesis of the corpus callosum.

Results: A common region of homozygosity on chromosome 8 spanning seven megabases (Mb) was identified in the affected individuals using the Illumina human cytoSNP-12 DNA Analysis BeadChip Kit. Exome sequencing identified a homozygous stop gain mutation (pR287X) in the phospholipase A1 gene DDHD2, in the affected individuals, resulting in a premature stop codon and a severely truncated protein lacking the SAM and DDHD domains crucial for phosphoinositide binding and phospholipase activity.

Conclusion: This mutation adds to the knowledge of HSP, suggests a possible founder effect for the pR287X mutation, and adds to the list of genes involved in lipid metabolism with a role in HSP and other neurodegenerative disorders.

No MeSH data available.


Related in: MedlinePlus

Pedigree structure of HSP family (SPG54) and sequence confirmation of the DDHD2 mutation. a Family pedigree. Squares and circles indicate males and females, respectively. Darkenedsymbols represent affected members, and slashes represent deceased. b Representative sequence traces of subjects and control. Sanger sequencing confirmed the homozygous nonsense mutation (c.859C >T, p.Arg287*) of the DDHD2 gene identified in the probands (IV-1, IV-3, IV-7, IV-8). The control sequence trace demonstrates the wild-type sequence. c A schematic illustration of DDHD2, showing four protein domains [WWE, lipase, coiled–coiled region (SAM), and DDHD]. The positions of all identified mutations are indicated. The mutation identified in this study is indicated in red.
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Fig1: Pedigree structure of HSP family (SPG54) and sequence confirmation of the DDHD2 mutation. a Family pedigree. Squares and circles indicate males and females, respectively. Darkenedsymbols represent affected members, and slashes represent deceased. b Representative sequence traces of subjects and control. Sanger sequencing confirmed the homozygous nonsense mutation (c.859C >T, p.Arg287*) of the DDHD2 gene identified in the probands (IV-1, IV-3, IV-7, IV-8). The control sequence trace demonstrates the wild-type sequence. c A schematic illustration of DDHD2, showing four protein domains [WWE, lipase, coiled–coiled region (SAM), and DDHD]. The positions of all identified mutations are indicated. The mutation identified in this study is indicated in red.

Mentions: The subjects who participated in the study are members of a Saudi Arabia based Indian family (Figure 1). Prior to commencement of the clinical and molecular investigations, informed consent was signed by the legal guardians, the parents, on behalf of the affected children and they agreed to publish the study outcomes. Ethical approval (ref. no. 24-14), according to the Declaration of Helsinki, was obtained from the Institutional Review Board (IRB), Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders and the Unit of Biomedical Ethics Research Committee, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. Peripheral or venous blood from six unaffected (III-1, III-2, III-3, III-4, IV-4, IV-5) and four affected (IV-1, IV-3, IV-7, IV-8) individuals was collected in EDTA tubes and stored at 4°C. Genomic DNA was extracted using QIAamp® mini DNA extraction kit (Qiagen, USA). The DNA was quantified by Nanodrop-2000 (Thermo Scientific, USA) spectrophotometer.Figure 1


Truncating mutation in intracellular phospholipase A₁ gene (DDHD2) in hereditary spastic paraplegia with intellectual disability (SPG54).

Alrayes N, Mohamoud HS, Jelani M, Ahmad S, Vadgama N, Bakur K, Simpson M, Al-Aama JY, Nasir J - BMC Res Notes (2015)

Pedigree structure of HSP family (SPG54) and sequence confirmation of the DDHD2 mutation. a Family pedigree. Squares and circles indicate males and females, respectively. Darkenedsymbols represent affected members, and slashes represent deceased. b Representative sequence traces of subjects and control. Sanger sequencing confirmed the homozygous nonsense mutation (c.859C >T, p.Arg287*) of the DDHD2 gene identified in the probands (IV-1, IV-3, IV-7, IV-8). The control sequence trace demonstrates the wild-type sequence. c A schematic illustration of DDHD2, showing four protein domains [WWE, lipase, coiled–coiled region (SAM), and DDHD]. The positions of all identified mutations are indicated. The mutation identified in this study is indicated in red.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4482296&req=5

Fig1: Pedigree structure of HSP family (SPG54) and sequence confirmation of the DDHD2 mutation. a Family pedigree. Squares and circles indicate males and females, respectively. Darkenedsymbols represent affected members, and slashes represent deceased. b Representative sequence traces of subjects and control. Sanger sequencing confirmed the homozygous nonsense mutation (c.859C >T, p.Arg287*) of the DDHD2 gene identified in the probands (IV-1, IV-3, IV-7, IV-8). The control sequence trace demonstrates the wild-type sequence. c A schematic illustration of DDHD2, showing four protein domains [WWE, lipase, coiled–coiled region (SAM), and DDHD]. The positions of all identified mutations are indicated. The mutation identified in this study is indicated in red.
Mentions: The subjects who participated in the study are members of a Saudi Arabia based Indian family (Figure 1). Prior to commencement of the clinical and molecular investigations, informed consent was signed by the legal guardians, the parents, on behalf of the affected children and they agreed to publish the study outcomes. Ethical approval (ref. no. 24-14), according to the Declaration of Helsinki, was obtained from the Institutional Review Board (IRB), Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders and the Unit of Biomedical Ethics Research Committee, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. Peripheral or venous blood from six unaffected (III-1, III-2, III-3, III-4, IV-4, IV-5) and four affected (IV-1, IV-3, IV-7, IV-8) individuals was collected in EDTA tubes and stored at 4°C. Genomic DNA was extracted using QIAamp® mini DNA extraction kit (Qiagen, USA). The DNA was quantified by Nanodrop-2000 (Thermo Scientific, USA) spectrophotometer.Figure 1

Bottom Line: Hereditary spastic paraplegias (HSP), a group of genetically heterogeneous neurological disorders with more than 56 documented loci (SPG1-56), are described either as uncomplicated (or pure), or complicated where in addition to spasticity and weakness of lower extremeties, additional neurological symptoms are present, including dementia, loss of vision, epilepsy, mental retardation and ichthyosis.Exome sequencing identified a homozygous stop gain mutation (pR287X) in the phospholipase A1 gene DDHD2, in the affected individuals, resulting in a premature stop codon and a severely truncated protein lacking the SAM and DDHD domains crucial for phosphoinositide binding and phospholipase activity.This mutation adds to the knowledge of HSP, suggests a possible founder effect for the pR287X mutation, and adds to the list of genes involved in lipid metabolism with a role in HSP and other neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, 80205, Kingdom of Saudi Arabia. nuharayes@gmail.com.

ABSTRACT

Background: Hereditary spastic paraplegias (HSP), a group of genetically heterogeneous neurological disorders with more than 56 documented loci (SPG1-56), are described either as uncomplicated (or pure), or complicated where in addition to spasticity and weakness of lower extremeties, additional neurological symptoms are present, including dementia, loss of vision, epilepsy, mental retardation and ichthyosis. We identified a large consanguineous family of Indian descent with four affected members with childhood onset HSP (SPG54), presenting with upper and lower limb spasticity, mental retardation and agenesis of the corpus callosum.

Results: A common region of homozygosity on chromosome 8 spanning seven megabases (Mb) was identified in the affected individuals using the Illumina human cytoSNP-12 DNA Analysis BeadChip Kit. Exome sequencing identified a homozygous stop gain mutation (pR287X) in the phospholipase A1 gene DDHD2, in the affected individuals, resulting in a premature stop codon and a severely truncated protein lacking the SAM and DDHD domains crucial for phosphoinositide binding and phospholipase activity.

Conclusion: This mutation adds to the knowledge of HSP, suggests a possible founder effect for the pR287X mutation, and adds to the list of genes involved in lipid metabolism with a role in HSP and other neurodegenerative disorders.

No MeSH data available.


Related in: MedlinePlus