Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes

Hufnagel, Robert B.; Arno, Gavin; Hein, Nichole D.; Hersheson, Joshua; Prasad, Megana; Anderson, Yvonne; Krueger, Laura A.; Gregory, Louise; Stoetzel, Corinne; Jaworek, Thomas; Hull, Sarah; Li, Abi; Plagnol, Vincent; Willen, Christi; Morgan, Thomas M.; Prows, Cynthia A.; Hegde, Rashmi S.; Riazuddin, Saima; Grabowski, Gregory A.; Richardson, Rudy J.; Dieterich, Klaus; Huang, Taosheng; Révész, Tamás; Martinez-Barbera, Juan Pedro; Sisk, Robert A.; Jefferies, Craig; Houlden, Henry; Dattani, Mehul; Fink, John K.; Dollfus, Hélène; Moore, Anthony T.; Ahmed, Zubair M.

doi:10.1136/jmedgenet-2014-102856

Cited by 99 publications

(95 citation statements)

References 44 publications

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“…Among the syndromes associated with mutations in PNPLA6 are: Gordon Holmes ( 22,23 ) and Boucher-Neuhauser ( 23 ), characterized by early-onset ataxia and hypogonadism; Oliver-McFarlane ( 24 ), characterized by trichomegaly, congenital hypopituitarism, retinal degeneration, and choroidal atrophy; Laurence-Moon ( 24 ), characterized by progressive spinocerebellar ataxia and spastic paraplegia; and photoreceptor degeneration and childhood blindness ( 25 ). An NTE-related iPLA 2 (PNPLA7) awaits further characterization ( 9, 10 ).…”

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confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

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The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

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confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

View full text Add to dashboard Cite

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“…Recently, it Lysosomal proteinase (cathepsin D) [8] was identified in Oliver-McFarlane syndrome, which adds trichological and pituitary abnormalities to the previous spectrum. Clinical presentation was shown to correlate with the degree of enzyme malfunction, with no activity in the latter [43].…”

Section: A Bumper Harvest Of Novel Genesmentioning

confidence: 97%

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

2015

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Hereditary cerebellar ataxias (HCAs) are clinically and genetically heterogeneous neurodegenerative disorders, characterised by a cerebellar syndrome and other neurological or non-neurological signs. So far, more than 20 genes have been described in autosomal dominant HCA; in autosomal recessive HCA, even more genes are involved, in often more complex phenotypes. Because of that complexity, the genetic diagnosis of these diseases is often based on the next-generation sequencing techniques. In this review paper, we discuss the major contributions that they have made to the genetic landscape of HCAs. Numerous novel genes have been identified; still more have recently been implicated in HCAs in addition to being responsible for other diseases. The phenotypic spectrum associated with a single gene constantly gains in complexity. Novel types of mutations or transmissions in known genes are regularly being identified. All these factors make genotype-phenotype correlations particularly difficult. Some but not all of this variability can be explained by different pathophysiological consequences (loss of function, gain of function, variable levels of haploinsufficiency). This also raises the question of modifier genes. Finally, we highlight some functional pathways that increasingly appear important in HCAs.

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“…5,6,19,20 A study of genotypephenotype correlations would be required to elucidate the molecular mechanisms underlying PNPLA6-related disorders.…”

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confidence: 99%

“…[5][6][7][14][15][16][17][18][19][20] Although a few mutations (p.S1045L, p.R1031fs*38, p.V1215A and p.G1129R) are shared with some families, most mutations are unique.…”

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confidence: 99%

Novel mutations in the PNPLA6 gene in Boucher-Neuhäuser syndrome

et al. 2015

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On whole-exome sequencing, a novel compound heterozygous mutation (c.2923A>G/c.3523_3524insTGTCCG, p.T975A/p.1175_1176insVS) and a novel homozygous one (c.3534G>C, p.W1178C) in the PNPLA6 gene were identified in sporadic and familial Japanese patients with Boucher-Neuhäuser syndrome (BNS), respectively. However, we did not find any mutations in the PNPLA6 gene in 88 patients with autosomal recessive hereditary spastic paraplegia (ARHSP). Our study confirmed the earlier report that a PNPLA6 mutation causes BNS. This is the first report on PNPLA6 mutations in non-Caucasian patients. Meanwhile, PNPLA6 mutations might be extremely rare in Japanese ARHSP patients. Moreover, we first found hypersegmented neutrophils in two BNS patients with PNPLA6 mutations.

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Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes

Cited by 99 publications

References 44 publications

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

Novel mutations in the PNPLA6 gene in Boucher-Neuhäuser syndrome

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