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Expression of PLA2G6 in human fetal development: Implications for infantile neuroaxonal dystrophy.

ABSTRACT: Mutations in PLA2G6, which encodes calcium-independent phospholipase A(2) group VIA (iPLA2-VIA), underlie the autosomal recessive disorder infantile neuroaxonal dystrophy (INAD). INAD typically presents in the first year of life, and leads to optic atrophy and psychomotor regression. We have examined PLA2G6 expression in early human embryonic development by in situ hybridization. At Carnegie Stage (CS) 19 (approximately 7 post-conception weeks [PCW]), strong expression is evident in the ventricular zone (VZ) of midbrain and forebrain suggestive of expression in neural stem and progenitor cells. At CS23 (8PCW) expression is also detectable in the VZ of the hindbrain and the subventricular zone (SVZ) of the developing neocortex, ganglionic eminences and diencephalon. By 9PCW strong expression in the post-mitotic cells of the cortical plate can be seen in the developing neocortex. In the eye, expression is seen in the lens and retina at all stages examined. PLA2G6 expression is also evident in the alar plate of the spinal cord, dorsal root ganglia, the retina and lens in the eye and several non-neuronal tissues, including developing bones, lung, kidney and gut. These findings suggest a role for PLA2G6 in neuronal proliferation throughout the developing brain and in maturing neurons in the cortical plate and hindbrain. Although widespread PLA2G6 expression is detected in neuronal tissues, the pattern shows dynamic changes with time and indicates that INAD pathogenesis may begin prior to birth.

SUBMITTER: Polster B

PROVIDER: S-EPMC2975838 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Expression of PLA2G6 in human fetal development: Implications for infantile neuroaxonal dystrophy.

Polster Brenda B Crosier Moira M Lindsay Susan S Hayflick Susan S

Brain research bulletin 20100909 6

Mutations in PLA2G6, which encodes calcium-independent phospholipase A(2) group VIA (iPLA2-VIA), underlie the autosomal recessive disorder infantile neuroaxonal dystrophy (INAD). INAD typically presents in the first year of life, and leads to optic atrophy and psychomotor regression. We have examined PLA2G6 expression in early human embryonic development by in situ hybridization. At Carnegie Stage (CS) 19 (approximately 7 post-conception weeks [PCW]), strong expression is evident in the ventricu ...[more]

PMID: 20813170

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Project description:BackgroundMutations in the PLA2G6 gene have been identified in autosomal recessive neurodegenerative diseases classified as infantile neuroaxonal dystrophy (INAD), neurodegeneration with brain iron accumulation (NBIA), and dystonia-parkinsonism. These clinical syndromes display two significantly different disease phenotypes. NBIA and INAD are very similar, involving widespread neurodegeneration that begins within the first 1-2 years of life. In contrast, patients with dystonia-parkinsonism present with a parkinsonian movement disorder beginning at 15 to 30 years of age. The PLA2G6 gene encodes the PLA2G6 enzyme, also known as group VIA calcium-independent phospholipase A(2), which has previously been shown to hydrolyze the sn-2 acyl chain of phospholipids, generating free fatty acids and lysophospholipids.Methodology/principal findingsWe produced purified recombinant wildtype (WT) and mutant human PLA2G6 proteins and examined their catalytic function using in vitro assays with radiolabeled lipid substrates. We find that human PLA2G6 enzyme hydrolyzes both phospholipids and lysophospholipids, releasing free fatty acids. Mutations associated with different disease phenotypes have different effects on catalytic activity. Mutations associated with INAD/NBIA cause loss of enzyme activity, with mutant proteins exhibiting less than 20% of the specific activity of WT protein in both lysophospholipase and phospholipase assays. In contrast, mutations associated with dystonia-parkinsonism do not impair catalytic activity, and two mutations produce a significant increase in specific activity for phospholipid but not lysophospholipid substrates.Conclusions/significanceThese results indicate that different alterations in PLA2G6 function produce the different disease phenotypes of NBIA/INAD and dystonia-parkinsonism. INAD/NBIA is caused by loss of the ability of PLA2G6 to catalyze fatty acid release from phospholipids, which predicts accumulation of PLA2G6 phospholipid substrates and provides a mechanistic explanation for the accumulation of membranes in neuroaxonal spheroids previously observed in histopathological studies of INAD/NBIA. In contrast, dystonia-parkinsonism mutations do not appear to directly impair catalytic function, but may modify substrate preferences or regulatory mechanisms for PLA2G6.

Project description:BACKGROUND:Infantile neuroaxonal dystrophy (INAD) is a rapidly progressive neurodegenerative disorder of early onset causing premature death. It results from biallelic pathogenic variants in PLA2G6, which encodes a calcium-independent phospholipase A2. OBJECTIVE:We aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings. MATERIALS AND METHODS:We comprehensively analyzed the charts of 28 patients: 16 patients from Riyadh, Saudi Arabia, 8 patients from North and South America and 4 patients from Europe with a molecularly confirmed diagnosis of PLA2G6-associated neurodegeneration (PLAN) and a clinical history consistent with INAD. RESULTS:In our cohort, speech impairment and loss of gross motor milestones were the earliest signs of the disease. As the disease progressed, loss of fine motor milestones and bulbar dysfunction were observed. Temporo-frontal function was among the last of the milestones to be lost. Appendicular spastic hypertonia, axial hypotonia, and hyperreflexia were common neurological findings. Other common clinical findings include nystagmus (60.7%), seizures (42.9%), gastrointestinal disease (42.9%), skeletal deformities (35.7%), and strabismus (28.6%). Cerebellar atrophy and elevations in serum AST and LDH levels were consistent features of INAD. There was a statistically significant difference when comparing patients with non-sense/truncating variants compared with missense/in-frame deletions in the time of initial concern (p?=?0.04), initial loss of language (p?=?0.001), initial loss of fine motor skills (p?=?0.009), and initial loss of bulbar skills (p?=?0.007). CONCLUSION:INAD is an ultra-rare neurodegenerative disorder that presents in early childhood, with a relentlessly progressive clinical course. Knowledge of the natural history of INAD may serve as a resource for healthcare providers to develop a targeted care plan and may facilitate the design of clinical trials to treat this disease.

Project description:BACKGROUND:INAD is an autosomal recessive neurogenetic disorder caused by biallelic pathogenic variants in PLA2G6. The downstream enzyme, iPLA2, plays a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids. The clinical presentation occurs between 6?months and 3?years with global developmental regression, hypotonia, and progressive spastic tetraparesis. Progression is often rapid, resulting in severe spasticity, visual impairment, and cognitive decline, with many children not surviving past the first decade of life. To date, no accepted tool for assessing the severity of INAD exists; other commonly used scales (e.g. CHOP-INTEND, Modified Ashworth, Hammersmith Functional Motor Scale) do not accurately gauge the current severity of INAD, nor are they sensitive/specific enough to monitor disease progression. Finally, these other scales are not appropriate, because they do not address the combination of CNS, peripheral nerve, and visual pathology that occurs in children with INAD. METHODS:We have developed and validated a structured neurological examination for INAD (scored out of 80). The examination includes six main categories of pediatric developmental evaluation: 1) gross motor-and-truncal-stability skills, 2) fine motor skills, 3) bulbar function, 4) ocular function, 5) temporo-frontal function, and, 6) Functional evaluation of the autonomic nervous system. A cohort of patients diagnosed with INAD were followed prospectively to validate the score against disease severity and disease progression. RESULTS:We show significant correlation between the total neurological assessment score and months since symptom onset with a statistically significant (p?=?6.7?×?10-?07) correlation between assessment score and disease onset. As hypothesized, the coefficient of months-since-symptom-onset is strongly negative, indicating a negative correlation between total score and months since symptom onset. CONCLUSION:We have developed and validated a novel neurological assessment score in INAD that demonstrates strong correlation with disease severity and disease progression.

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Expression of PLA2G6 in human fetal development: Implications for infantile neuroaxonal dystrophy.

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Expression of PLA2G6 in human fetal development: Implications for infantile neuroaxonal dystrophy.

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