RT Journal Article
SR Electronic
T1 Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 85
OP 94
DO 10.1136/jmedgenet-2014-102856
VO 52
IS 2
A1 Robert B Hufnagel
A1 Gavin Arno
A1 Nichole D Hein
A1 Joshua Hersheson
A1 Megana Prasad
A1 Yvonne Anderson
A1 Laura A Krueger
A1 Louise C Gregory
A1 Corinne Stoetzel
A1 Thomas J Jaworek
A1 Sarah Hull
A1 Abi Li
A1 Vincent Plagnol
A1 Christi M Willen
A1 Thomas M Morgan
A1 Cynthia A Prows
A1 Rashmi S Hegde
A1 Saima Riazuddin
A1 Gregory A Grabowski
A1 Rudy J Richardson
A1 Klaus Dieterich
A1 Taosheng Huang
A1 Tamas Revesz
A1 J P Martinez-Barbera
A1 Robert A Sisk
A1 Craig Jefferies
A1 Henry Houlden
A1 Mehul T Dattani
A1 John K Fink
A1 Helene Dollfus
A1 Anthony T Moore
A1 Zubair M Ahmed
YR 2015
UL http://jmg.bmj.com/content/52/2/85.abstract
AB Background Oliver–McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence–Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. Methods Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. Results Eight mutations in six families with Oliver–McFarlane or Laurence–Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver–McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver–McFarlane and Laurence–Moon syndromes revealed extensive cerebellar degeneration and atrophy. Conclusions Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon–Holmes syndrome and Boucher–Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.