Alternative titles; symbols
HGNC Approved Gene Symbol: PNPLA6
SNOMEDCT: 232059000, 5619004, 715984007, 719103009, 719944006; ICD10CM: Q87.84;
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:7,534,164-7,561,767 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | ?Laurence-Moon syndrome | 245800 | Autosomal recessive | 3 |
| Boucher-Neuhauser syndrome | 215470 | Autosomal recessive | 3 | |
| Oliver-McFarlane syndrome | 275400 | Autosomal recessive | 3 | |
| Spastic paraplegia 39, autosomal recessive | 612020 | Autosomal recessive | 3 |
The PNPLA6 gene encodes an enzyme that catalyzes the deesterification of membrane phosphatidylcholine into fatty acids and glycerophosphocholine (summary by Synofzik et al., 2014).
Covalent modification of neuropathy target esterase (NTE) by certain organophosphorus esters (OPs) leads, after a delay of several days, to a degeneration of long axons in the spinal cord and peripheral nerves. Lush et al. (1998) determined a partial protein sequence of pig NTE. They searched an EST database and identified a human cDNA that encodes a polypeptide showing homology to 1 of the pig NTE peptides. Using this cDNA as a probe, the authors screened a human fetal brain cDNA library and isolated a cDNA containing the entire NTE coding sequence. The deduced 1,327-amino acid protein contains 4 predicted transmembrane domains and multiple potential sites for N- and O-linked glycosylation. SDS-PAGE and biochemical analyses showed that human NTE is a glycoprotein with an apparent molecular mass of 155 kD. NTE shares 41% amino acid sequence identity with the Drosophila 'Swiss Cheese' (Sws) protein, which is involved in the regulation of interactions between neurons and glia in the developing fly brain.
Hufnagel et al. (2015) studied the expression of PNPLA6 during human central nervous system and retina development. In embryonic tissues, PNPLA6 expression was found throughout the neural retina, retinal pigment epithelium, choroid, anterior and posterior pituitary, cerebellum, and ventricular zones of the developing brain. Expression was also detected in the epidermis, lens, extraocular muscles, nasal epithelium, trigeminal ganglion, and diencephalon. PNPLA6 expression was also observed in all adult human and mouse tissues tested.
In the positional cloning of the mucolipidosis IV gene (MCOLN1; 605248), which maps to 19p13.3-p13.2, Bargal et al. (2000) found that the NTE gene is located in this region. They analyzed all 33 coding exons of this gene in 6 mucolipidosis IV patients and identified no mutations.
By FISH, Winrow et al. (2003) demonstrated that the Nte locus maps to mouse chromosome 8A1.1 and the human NTE gene maps to 19p13.3.
Spastic Paraplegia 39, Autosomal Recessive
Rainier et al. (2008) described 2 families, one consanguineous, in which affected subjects exhibited progressive spastic paraplegia and distal muscle wasting (SPG39; 612020). Affected subjects resembled those with OPIDN and those with Troyer syndrome (275900) due to SPG20 (607111) gene mutation. The latter possibility was excluded by genetic linkage and sequence analysis of the SPG20 gene. Genomewide analysis suggested linkage to a 22-cM homozygous locus on 19p13 to which NTE had been mapped. The pathogenesis of organophosphorous (OP) compound-induced delayed neuropathy (OPIDN) involves neuropathy target esterase (NTE), a neuronal membrane protein, either through direct OP-induced inhibition of NTE or through generation of OP-NTE neurotoxic complexes ('aged NTE'). NTE was a candidate because of its role in OPIDN and the similarity of the patients to those with OPIDN. Affected subjects in the consanguineous kindred were homozygous for a disease-specific NTE mutation, 3034A-G, that disrupted an interspecies-conserved residue in NTE's catalytic domain (M1012V; 603197.0001). Affected subjects in the nonconsanguineous family were compound heterozygotes: 1 allele carried a 2669G-A mutation that disrupted an interspecies-conserved residue in NTE's catalytic domain (R890H; 603197.0002), and the other allele had an insertion that caused frameshift and protein truncation (603197.0003). Disease-specific, nonconserved NTE mutations in unrelated patients with motor neuron disease (MND) indicated the importance of NTE in maintaining axonal integrity, raised the possibility that NTE pathway disturbances contribute to other MNDs including amyotrophic lateral sclerosis (ALS; see 105400), and supported the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds.
In 2 of 538 unrelated patients with ataxia, spastic paraplegia, or neuropathy who underwent sequencing of the PNPLA6 gene, Synofzik et al. (2014) identified compound heterozygous mutations in the PNPLA6 gene (see, e.g., 603197.0009 and 603197.0010). One patient was diagnosed with spastic paraplegia and mild motor neuropathy, and the other was diagnosed with spastic ataxia. The phenotype in both patients was consistent with SPG39.
Boucher-Neuhauser Syndrome
In 9 patients from 4 unrelated families with Boucher-Neuhauser syndrome (BNHS; 215470), Synofzik et al. (2014) identified homozygous or compound heterozygous mutations in the PNPLA6 gene (see, e.g., 603197.0004-603197.0008). All mutations occurred at highly conserved residues and were predicted to disrupt protein function, but in vitro functional studies of the variants were not performed. The mutations in the first 2 families were found by whole-exome sequencing, whereas mutations in the second 2 families were found by direct sequencing of the PNPLA6 gene in 4 additional families with the disorder. A patient from a fifth family who did not have chorioretinopathy also carried biallelic PNPLA6 mutations. The disorder in most patients was characterized by the triad of spinocerebellar ataxia, hypogonadotropic hypogonadism, and visual impairment due to chorioretinal dystrophy. The age at onset was variable, but most patients developed one or more symptoms in the first decade of life. Two patients did not have chorioretinal dystrophy. Synofzik et al. (2014) concluded that BNHS is part of a spectrum of neurodegenerative diseases associated with mutations in the PNPLA6 gene that also includes SPG39.
In 6 patients from 3 unrelated families with BNHS, Topaloglu et al. (2014) identified homozygous or compound heterozygous mutations in the PNPLA6 gene (see, e.g., 603197.0011-603197.0012). The mutation in the first family was found by homozygosity mapping and whole-exome sequencing; subsequent mutations were found by direct sequencing of the PNPLA6 gene in 5 additional families. The mutations failed to rescue the neurodegenerative 'Sws' vacuolization phenotype in Drosophila with loss of Pnpla6. Inhibition of NTE activity in a mouse gonadotrope cell line inhibited GNRH (152760)-stimulated luteinizing hormone (LH) exocytosis, without affecting GNRH receptor (GNRHR; 138850) signaling or LH-beta (LHB; 152780) synthesis. The findings were consistent with the mutations resulting in a loss of function. Some patients did not have chorioretinopathy, a finding more consistent with a clinical diagnosis of Gordon Holmes syndrome (GDHS; 212840); Topaloglu et al. (2014) noted that GDHS and BNHS are related disorders.
Oliver-McFarlane Syndrome
In 6 patients from 5 families with a clinical diagnosis of Oliver-McFarlane syndrome (OMCS; 275400), Hufnagel et al. (2015) identified compound heterozygous mutations in the PNPLA6 gene (see, e.g., 603197.0013-603197.0016). The mutations were found in 3 families by exome sequencing and in the other 2 families by Sanger sequencing. Familial carrier testing, which was possible in 3 families, showed segregation of the mutation with the phenotype. Fibroblast cells from patients and heterozygous parents in 1 family showed reduced NTE hydrolase activity compared with controls. Patient fibroblast cells also showed a significant reduction in NTE-mediated hydrolysis compared with those from patients with SPG39.
Laurence-Moon Syndrome
In affected members of a family with a clinical diagnosis of Laurence-Moon syndrome (LNMS; 245800), originally reported by Chalvon-Demersay et al. (1993), Hufnagel et al. (2015) identified compound heterozygous mutations in the PNPLA6 gene (603197.0013; 603197.0017). The mutations, which were found by exome sequencing, segregated with the disorder in the family. The mutations were not found in over 300 ethnically matched controls or in the 1000 Genomes Project or Exome Variant Server databases.
Mutations in PNPLA6, encoding neuropathy target esterase (NTE), cause the autosomal recessive disorders spastic paraplagia-39 (SPG39; 612020), Boucher-Neuhauser syndrome (BNHS; 215470), Laurence-Moon syndrome (LNMS; 245800), and Oliver-MacFarlane syndrome (OMCS; 275400), which together exhibit significant pleiotropy involving the central and peripheral nervous system and with endocrine, ophthalmic, and hair anomalies. Liu et al. (2024) correlated PNPLA6 genotype with NTE activity and phenotype. Mutations in the PNPLA6 NEST domain, which contains the catalytic residues necessary for phospholipid remodeling, were observed more frequently in individuals with retinopathy and endocrinopathy. Enzymatic assays showed that the NTE activity of all disease-causing missense, inframe, or truncating variants tested was significantly reduced compared to wildtype control, and truncating variants that disrupted the NEST domain produced no NTE hydrolase activity. Truncations before amino acid 1177 produced no NTE activity, while truncations past this position produced relatively high residual esterase activity. The estimated residual activity of biallelic variants calculated together correlated with disease severity and the presence of retinopathy or endocrinopathy, but there was no relationship to age of onset. NTE activity was found to drive retinal degeneration in mice (see ANIMAL MODEL). Liu et al. (2024) concluded that the presence of affected tissues in disorders caused by PNPLA6 mutations is determined by residual protein activity.
NTE is involved in neuronal development and is the target for neurodegeneration induced by selected organophosphorus pesticides and chemical warfare agents. Winrow et al. (2003) generated mice with disruption in Nte. Nte -/- mice died after embryonic day 8, and heterozygous Nte +/- mice had lower activity of Nte in the brain and higher mortality when exposed to an Nte-inhibiting compound (EOPF) than did wildtype mice. Nte +/- and wildtype mice treated with 1 mg per kg of body weight of EOPF had elevated motor activity, showing that even minor reduction of Nte activity leads to hyperactivity. Studies showed that genetic or chemical reduction of Nte activity results in a neurologic phenotype of hyperactivity in mammals and indicated that EOPF toxicity occurs directly through inhibition of Nte without the requirement for Nte gain of function or aging.
O'Callaghan (2003) interpreted the significance of the studies of Winrow et al. (2003) in relation to the toxicity of organophosphates, which have long been used as pesticides and which are a concern because of their potential use as chemical warfare agents. As a class of compounds, organophosphate esters inhibit serine-containing esterases owing to phosphorylation of serine residues at the active site of these enzymes, the most notable of which is acetylcholinesterase (100740). Most features of the acute toxicity of these compounds relate to their inhibition of this enzyme. A less well known feature of some organophosphates is their propensity to cause a delayed neuropathy that has been termed organophosphate-induced delayed neurotoxicity (OPIDN). This is a progressive neurologic condition characterized by weakness, ataxia, and subsequent paralysis of the limbs. The major neuropathologic hallmarks of OPIDN are degeneration of the long exons of the spinal cord and peripheral neurons. The proposed target for initiation of OPIDN has been NTE. The mechanistic basis for initiation of OPIDN through NTE was thought to involve the generation of an 'aged' form of the enzyme. The work of Winrow et al. (2003) provided evidence against the aging concept without ruling out involvement of NTE itself. Mice deficient in the enzyme should be less susceptible to toxicity, but the opposite turned out to be the case.
Moser et al. (2004) observed lethality in Nte-null mouse embryos after gastrulation at embryonic day 9 postcoitum. As early as embryonic day 7.5, mutant embryos showed growth retardation which did not reflect impaired cell proliferation but resulted from failed placental development; as a consequence, massive apoptosis within the developing embryo preceded its resorption. Histologic analysis indicated that NTE is essential for the formation of the labyrinth layer and the survival and differentiation of secondary giant cells. Impaired vasculogenesis in the yolk sacs and embryos of null mutant conceptuses suggested that NTE is also required for normal blood vessel development.
Liu et al. (2024) generated Pnpla6 mutant mice carrying a mutation (MV) corresponding to the M1012V mutation (603197.0001) found only in SPG39 patients and a truncating mutation (delAT) that exhibits no residual activity due to truncation prior to the enzymatic domain. Mice carrying the MV allele were viable and born at mendelian ratios, but delAT homozygous mice were not viable. There was no significant difference in photopic and scotopic a- and b-wave amplitudes between control and MV/MV mice, which recapitulated the eye phenotype in SPG39 patients, who do not have a retinopathy phenotype. There was a significant reduction in amplitudes between control and MV/delAT mice. Control and MV/MV mice did not show significant differences in visual acuity (p = 0.80), but MV/delAT mice had significantly reduced visual acuity compared to controls (p = 0.008). Retinal thickness was significantly reduced in MV/delAT mice compared to controls, but not in MV/MV mice. The outer nuclear layer (ONL) was consistently thinner at all time points after 3 months of age in MV/delAT mice compared to controls, but not in MV/MV mice. Analysis of NTE activity in mouse brain indicated that less than 40% NTE activity was embryonic lethal, and that the onset of retinal degeneration occurs between 40 and 50% residual activity, consistent with overall NTE activity levels in patients with retinopathy.
In a consanguineous family of Ashkenazi Jewish ancestry, Rainier et al. (2008) demonstrated an association between motor neuron disease (SPG39; 612020) and homozygosity for a missense mutation in the NTE gene: c.3034A-G, met1012 to val (M1012V).
Liu et al. (2024) numbered this mutation M1060V (c.3178A-G, NM_001166111.2).
By NTE hydrolase assay, Liu et al. (2024) determined that M1060V mutant protein has 79% activity of wildtype.
In a nonconsanguineous family, Rainier et al. (2008) found that motor neuron disease (SPG39; 612020) was associated with compound heterozygosity for 2 mutations in the NTE gene. On 1 allele the 2 affected individuals carried a G-to-A transition at cDNA position 2669 that resulted in substitution of histidine for arginine at codon 890 (R890H); the other allele carried a 4-bp insertion (603197.0003). The affected individuals were brother and sister, and inherited the missense mutation from the father and the insertion from the mother.
Liu et al. (2024) numbered this mutation R938H (c.2813G-A, NM_001166111.2).
By NTE hydrolase assay, Liu et al. (2024) determined that R938H mutant protein has 85% activity of wildtype.
The 2 affected individuals with motor neuron disease (SPG39; 612020) in the nonconsanguineous family described by Rainier et al. (2008) carried a 4-bp insertion on the maternal allele, c.2946_2947insCAGC, that caused frameshift and protein truncation (Ser982fs1019). The paternal allele carried a missense mutation (603197.0002).
In 4 adult sibs, born of consanguineous Brazilian parents, with Boucher-Neuhauser syndrome (BNHS; 215470), Synofzik et al. (2014) identified a homozygous c.3173C-T transition in the PNPLA6 gene, resulting in a thr1058-to-ile (T1058I) substitution at a highly conserved residue in the phospholipase esterase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 137) or Exome Variant Server databases. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed. The patients had onset of visual impairment due to chorioretinal dystrophy in the first few years of life. Gait ataxia began around age 6 to 7, and all had hypogonadotropic hypogonadism. Other features included hyporeflexia, distal muscle wasting, cerebellar atrophy, and mild cognitive impairment.
By NTE hydrolase assay, Liu et al. (2024) determined that T1058I mutant protein has 31% activity of wildtype.
In 2 adult Italian sisters with Boucher-Neuhauser syndrome (BNHS; 215470), Synofzik et al. (2014) identified compound heterozygous mutations in the PNPLA6 gene: a G-to-C transversion in intron 19 (c.2212-1G-C), predicted to result in a splice site alteration and premature termination (Val738GlnfsTer98), and a c.3328G-A transition, resulting in a val1110-to-met (V1110M; 603197.0006) substitution in the phospholipase esterase domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the dbSNP (build 137) or Exome Variant Server databases. Each unaffected parent was heterozygous for 1 of the mutations. Functional studies of the variants were not performed. Both patients had hypogonadism, but only 1 had chorioretinal dystrophy. One developed gait ataxia at age 6, and the other at age 27. Both also had spasticity with extensor plantar responses and mild cognitive impairment. Synofzik et al. (2014) emphasized the intrafamilial variability, particularly with regard to visual impairment.
Liu et al. (2024) estimated the residual activity of the V738QfsX98 and V1110M mutations together to be 11% of wildtype.
For discussion of the val1110-to-met (V1110M) mutation in the PNPLA6 gene that was found in compound heterozygous state in patients with Boucher-Neuhauser syndrome (BNHS; 215470) by Synofzik et al. (2014), see 603197.0005.
In 2 adult Brazilian brothers with Boucher-Neuhauser syndrome (BNHS; 215470), Synofzik et al. (2014) identified compound heterozygous mutations in the PNPLA6 gene: a c.1732G-T transversion, resulting in a gly578-to-trp (G578W) substitution at a highly conserved residue in the CNB2 regulatory domain, and a c.3197T-C transition, resulting in a phe1066-to-ser (F1066S; 603197.0008) substitution at a highly conserved residue in the phospholipid esterase domain. Neither mutation was found in the dbSNP (build 137) or Exome Variant Server databases. Functional studies of the variants were not performed. Both patients presented with gait ataxia at age 6 years, and later showed hypogonadotropic hypogonadism and chorioretinal dystrophy. One patient had mild spasticity.
For discussion of the phe1066-to-ser (F1066S) mutation in the PNPLA6 gene that was found in compound heterozygous state in patients with Boucher-Neuhauser syndrome (BNHS; 215470) by Synofzik et al. (2014), see 603197.0007.
In a 54-year-old German woman with autosomal recessive spastic paraplegia-39 (SPG39; 612020), Synofzik et al. (2014) identified compound heterozygous mutations in the PNPLA6 gene: a c.787G-A transition, resulting in a val263-to-ile (V263I) substitution at a highly conserved residue in the CNB1 (601302) regulatory domain, and a c.2519G-A transition, resulting in a gly840-to-glu (G840E; 603197.0010), substitution at a highly conserved residue in the phospholipid esterase domain. Neither mutation was found in the dbSNP (build 137) or Exome Variant Server databases. Functional studies of the variants were not performed. The patient presented with spasticity at age 20 years but had no additional features of the disease.
By NTE hydrolase assay, Liu et al. (2024) determined that V263I mutant protein has 41% activity of wildtype, and G840E 40% of wildtype.
For discussion of the gly840-to-glu (G840E) mutation in the PNPLA6 gene that was found in compound heterozygous state in a woman with autosomal recessive spastic paraplegia-39 (SPG39; 612020) by Synofzik et al. (2014), see 603197.0009.
In 2 Dutch sibs with Boucher-Neuhauser syndrome (BNHS; 215470), originally reported by Rump et al. (1997), Topaloglu et al. (2014) identified compound heterozygous mutations in the PNPLA6 gene: a 1-bp insertion (c.1127insG, NM_006702), resulting in a frameshift and premature termination (Asp376GlyfsTer18), and a c.3295C-T transition, resulting in an arg1099-to-cys (R1099C; 603197.0012) substitution. The truncated protein is predicted to lack the entire catalytic domain and the C-terminal portion of the regulatory domain. Each unaffected parent was heterozygous for 1 of the mutations, which were not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases or in 100 matched control individuals.
Liu et al. (2024) referred to the consequence of the c.1127insG mutation as D424EfsX18 and to the R1099C mutation as R1147C (c.3439C-T, NM_001166111.2).
Liu et al. (2024) estimated the residual activity of the D424EfsX18 and R1099C mutations together to be 22% of wildtype.
For discussion of the arg1099-to-cys (R1099C) mutation (c.3295C-T, NM_006702) in the PNPLA6 gene that was found in compound heterozygous state in patients with Boucher-Neuhauser syndrome (BNHS; 215470) by Topaloglu et al. (2014), see 603197.0011.
Oliver-McFarlane Syndrome
In affected members of 2 unrelated families (B and E) with a clinical diagnosis of Oliver-McFarlane syndrome (OMCS; 275400), one of which was originally reported by Patton et al. (1986), Hufnagel et al. (2015) identified compound heterozygous mutations in the PNPLA6 gene: a 4-bp insertion (c.3091_3092insAGCC, NM_001166111.1) resulting in a frameshift and premature termination (Arg1031fsTer38, R1031fsX38), on 1 allele, and a gly1129-to-arg missense mutation (G1129R; 603197.0014) on the other allele. The mutations were not found in over 300 ethnically matched controls or in the Exome Variant Server or 1000 Genomes Project databases.
By NTE hydrolase assay, Liu et al. (2024) determined that the G1129R mutant PNPLA6 protein has 57% activity of wildtype. They estimated the residual activity of the R1031QfsX38 and G1129R mutations together to be 29% of wildtype.
Laurence-Moon Syndrome
In affected members of a family (F) with a clinical diagnosis of Laurence-Moon syndrome (LNMS; 245800), originally reported by Chalvon-Demersay et al. (1993), Hufnagel et al. (2015) identified compound heterozygous mutations in the PNPLA6 gene: the 4-bp insertion and a gly726-to-arg (G726R; 603197.0017) substitution. The mutations, which were found by exome sequencing, segregated with the disorder in the family. The G726R mutation was not found in over 300 ethnically matched controls or in the 1000 Genomes Project or Exome Variant Server databases.
By NTE hydrolase assay, Liu et al. (2024) determined that the G726R mutant PNPLA6 protein has 61% activity of wildtype. They estimated the residual activity of the R1031QfsX38 and G726R mutations together to be 31% of wildtype.
For discussion of the gly1129-to-arg (G1129R) mutation in the PNPLA6 gene that was found in compound heterozygous state in patients with a clinical diagnosis of Oliver-McFarlane syndrome (OMCS; 275400) by Hufnagel et al. (2015), see 603197.0013.
By whole-exome sequencing in 2 affected members of a family (A) segregating Oliver-McFarlane syndrome (OMCS; 275400), Hufnagel et al. (2015) identified compound heterozygosity for 2 missense mutations in the PNPLA6 gene: a c.3526G-A transition (rs142422525) resulting in a gly1176-to-ser (G1176S) substitution, and an arg1099-to-gln (R1099Q; 603197.0016) substitution. The mutations segregated with the disorder in the family. The G1176S mutation was found once in over 13,000 alleles in the Exome Variant Server database but was not found in the 1000 Genomes Project database; the R1099Q mutation was not found in either of the databases. Fibroblast cells from patients and heterozygous parents in this family showed reduced NTE hydrolase activity compared with controls. Patient cells also had significantly reduced NTE specific activity compared with cells from patients with SPG39 who were homozygous for the M1012V mutation in the PNPLA6 gene (603197.0001).
By NTE hydrolase assay, Liu et al. (2024) determined that the G1176S mutant PNPLA6 protein has 19% activity of wildtype, and R1099Q 28% of wildtype. They estimated the residual activity of the G1176S and R1099Q mutations together to be 24% of wildtype.
For discussion of the arg1099-to-gln (R1099Q) mutation that was found in compound heterozygous state in patients with a clinical diagnosis of Oliver-McFarlane syndrome (OMCS; 275400) by Hufnagel et al. (2015), see 603197.0015.
For discussion of the gly726-to-arg (G726R) mutation that was found in compound heterozygous state in a patient with a clinical diagnosis of Laurence-Moon syndrome (LNMS; 245800) by Hufnagel et al. (2015), see 603197.0013.
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