Alternative titles; symbols
HGNC Approved Gene Symbol: PLCB4
Cytogenetic location: 20p12.3-p12.2 Genomic coordinates (GRCh38): 20:9,068,678-9,480,808 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p12.3-p12.2 | Auriculocondylar syndrome 2A | 614669 | Autosomal dominant | 3 |
| Auriculocondylar syndrome 2B | 620458 | Autosomal recessive | 3 |
In the phosphoinositide (PI) cycle, phospholipase C (PLC) catalyzes hydrolysis of a plasma membrane phospholipid, phosphatidylinositol 4,5-bisphosphate, generating 2 second messengers, the water soluble 1,4,5-inositol trisphosphate and the membrane-associated 1,2-diacylglycerol. In mammalian tissues, several groups of PLCs have been characterized, including PLC-beta, and each group contains at least 3 isoforms. These proteins are single polypeptides, ranging in molecular mass from 65 to 154 kD (summary by Alvarez et al., 1995).
Alvarez et al. (1995) isolated several overlapping cDNA clones from a human retina library. The composite cDNA sequence predicted a human PLC-beta-4 polypeptide of 1,022 amino acid residues with a molecular mass of 117 kD. This PLC-beta-4 variant lacked the 165-amino acid N-terminal domain characteristic of the rat brain isoforms, but had a distinct putative exon 1 unique for human and bovine retina isoforms. A PLC-beta-4 monospecific antibody detected a major (130 kD) and a minor (160 kD) isoform in retina homogenates. The PLC-beta isozymes appear to be unique in their activation by G proteins. PLCB4 is expressed in rat brain, bovine cerebellum, and bovine retina in several splice variants.
Alvarez et al. (1995) used somatic cell hybrids and deletion panels to localize the PLCB4 gene to the short arm of chromosome 20. The gene was further sublocalized to 20p12 by fluorescence in situ hybridization.
Alvarez et al. (1995) noted that several lines of evidence suggested signal transduction via the PI cycle plays a role in the light response in vertebrate and invertebrate retinas. Defects in the Drosophila norpA ('no receptor potential A') gene encoding a phosphoinositide-specific PLC block invertebrate phototransduction and lead to retinal degeneration.
Phospholipase C beta-4 is expressed in the suprachiasmatic nucleus (SCN) in the mouse. Park et al. (2003) showed that PLCB4 -/- mice had a pronounced loss of persistent circadian rhythm under constant darkness and a significantly decreased spontaneous firing rate of suprachiasmatic neurons during the subjective day. Antagonist studies showed that PLCB4 is coupled to metabotropic glutamate receptors (see 604473) in the SCN, and that this signaling pathway is involved in translating circadian oscillations of the molecular clock into rhythmic outputs of SCN neurons.
Xue et al. (2011) reported that an intrinsic component of the pupillary light reflex (PLR) is widespread in nocturnal and crepuscular mammals. In mouse, this intrinsic PLR requires the visual pigment melanopsin (606665); it also requires PLC-beta-4, a vertebrate homolog of the Drosophila NorpA phospholipase C which mediates rhabdomeric phototransduction. The Plcb4 -/- genotype, in addition to removing the intrinsic PLR, also essentially eliminates the intrinsic light response of the M1 subtype of melanosin-expressing intrinsically photosensitive retinal ganglion cells (M1-ipRGCs), which are by far the most photosensitive ipRGC subtype and also have the largest response to light. Ablating in mouse the expression of both TRPC6 (603652) and TRPC7 (603749), members of the TRP channel superfamily, also essentially eliminated the M1-ipRGC light response, but the intrinsic PLR was not affected. Thus, Xue et al. (2011) concluded that melanopsin signaling exists in both iris and retina, involving a PLC-beta-4-mediated pathway that nonetheless diverges in the 2 locations.
Auriculocondylar Syndrome 2A
By whole-exome sequencing, Rieder et al. (2012) identified heterozygous missense mutations in the PLCB4 gene (600810.0001 and 600810.0002) in 2 probands with auriculocondylar syndrome (ARCND2A; 614669). Subsequent Sanger sequencing of PLCB4 gene-coding regions containing the conserved catalytic site (exons 11-26) in the probands from 3 unrelated multigenerational ARCND pedigrees revealed 3 more heterozygous missense mutations (600810.0003-600810.0005) Functional analysis demonstrated a significant reduction of downstream targets of the G protein-coupled endothelin receptor pathway in mutant cultured mandibular osteoblasts compared to controls.
Gordon et al. (2013) analyzed the PLCB4 and GNAI3 genes in 27 patients, including 8 with clinical ARCND, 5 with 'atypical' ARCND who were previously described by McGowan et al. (2011), 3 with isolated question mark ears (612798), 6 diagnosed with either oculoauriculovertebral syndrome (OAVS) or Goldenhar syndrome (see hemifacial microsomia, 164210), and 4 with nonsyndromic auricular dysplasia with or without mandibular dysplasia. They identified 6 heterozygous missense mutations in the PLCB4 gene in 6 patients with ARCND (600810.0003, 600810.0004, and 600810.0006-600810.0009), including patients previously reported by Gerkes et al. (2008), Stuffken and Tuinzing (2008), and Greig et al. (2012), as well as in a proband previously described as having isolated question mark ears (Shkalim et al., 2008). A heterozygous missense mutation was identified in the GNAI3 gene (139370.0002) in 1 patient with ARCND (ARCND1; 603483). Gordon et al. (2013) noted that of 15 reported mutation-positive ARCND patients, 12 (80%) had a mutation in PLCB4 and 3 (20%) had a mutation in GNAI3. In addition, they noted apparent hotspots in the PLCB4 gene, with 5 of 11 reported point mutations occurring at R621 (e.g., 600810.0003, 600810.0004, and 600810.0006) and 2 at D360 (600810.0008-600810.0009).
Romanelli Tavares et al. (2017) analyzed the GNAI3, PLCB4, and EDN1 (131240) genes in 3 probands with typical auriculocondylar syndrome and 8 patients with features overlapping those of ARCND. They identified heterozygous missense mutations in the PLCB4 gene in 2 of the typical ARCND probands (E358Q, 600810.0014 and H328R, 600810.0015) that were not found in public variant databases. No pathogenic variants were detected in any other patient.
In affected members of a 3-generation Egyptian family with ARCND, Nabil et al. (2020) identified heterozygosity for the previously reported R621H substitution in the PLCB4 gene (600810.0003) that segregated fully with disease in the pedigree. The authors noted that ARCND is a rare disorder that poses a diagnostic challenge due to its highly variable clinical presentation and apparent lack of genotype-phenotype correlation.
Vegas et al. (2022) reviewed 9 previously described patients and reported 10 new patients from 6 families with ARCND and heterozygous mutations in the PLCB4 gene (see, e.g., 600810.0003 and 600810.0004). The authors noted that all heterozygous missense mutations affected the catalytic domain of the protein and were predicted to act via a dominant-negative mechanism. In addition, there appeared to be a hotspot at PLCB4 codon 621, with R621H (600810.0003), R621C (600810.0004), and R621L (600810.0006) substitutions having been reported in multiple families.
Auriculocondylar Syndrome 2B
In a male proband (case 8) from a consanguineous Indian family with auriculocondylar syndrome and macropenis (ARCND2B; 620458), Gordon et al. (2013) identified a large homozygous deletion in the PLCB4 gene (600810.0010). The unaffected status of his heterozygous parents was cited by Gordon et al. (2013) as further support for a dominant-negative mechanism of ARCND-associated point mutations rather than haploinsufficiency.
In 2 Japanese brothers with auriculocondylar syndrome, gastroesophageal reflux, chronic constipation, and macropenis, Kido et al. (2013) identified compound heterozygosity for splice site mutations in the PLCB4 gene (600810.0011 and 600810.0012). Their unaffected parents were each heterozygous for 1 of the mutations, which were not found in public variant databases.
In a 6-year-old girl with auriculocondylar syndrome, gastroesophageal reflux, chronic constipation, and clitoral hypertrophy, Leoni et al. (2016) identified homozygosity for a 1-bp deletion in the PLCB4 gene (600810.0013). Her unaffected parents were heterozygous for the deletion, which was not found in public variant databases.
Vegas et al. (2022) reviewed 3 previously described patients with biallelic PLCB4 mutations and reported a 4.5-year-old Turkish girl (patient 23) with auriculocondylar syndrome, severe mixed sleep apnea, feeding difficulties, and developmental delay who was homozygous for a 1-bp duplication in the PLCB4 gene (600810.0016). Her unaffected consanguineous parents were heterozygous for the duplication.
Kim et al. (1997) found that Plcb4-null mice showed retarded postnatal growth and low viability, and developed a motor defect consistent with ataxia. They were hypokinetic and showed a waddling gait. Histologic studies showed cerebellar hypoplasia with aberrant patterns of folia and incomplete migration of external granule cells. There was also impaired signaling via metabotropic glutamate receptors (mGluR) and muscarinic acetylcholine receptors (mAChR). The findings suggested that Plcb4 mediates signaling in the cerebellum through specific receptors.
In a female patient with auriculocondylar syndrome (ARCND2A; 614669), Rieder et al. (2012) identified heterozygosity for a de novo c.1868A-G transition (c.1868A-G, NM_000933.3) in the PLCB4 gene, resulting in a tyr623-to-cys (Y623C) substitution at a highly conserved residue. The mutation was not present in her unaffected parents or in 10,758 control chromosomes. The effects of the Y623C substitution were evaluated by assaying expression of known downstream targets in the G protein-coupled endothelin receptor pathway, DLX5 (600028) and DLX6 (600030), in cultured mandibular osteoblasts: 6-fold and 8-fold reductions in DLX5 and DLX6 expression, respectively, were demonstrated in mutant samples compared to controls.
In a brother and sister with auriculocondylar syndrome (ARCND2A; 614669), Rieder et al. (2012) identified heterozygosity for a c.986A-G transition (c.986A-G, NM_000933.3) in the PLCB4 gene, resulting in an asn329-to-ser (N329S) substitution at a highly conserved residue. Their mildly affected father, who had only mild mandibular hypoplasia, was also heterozygous for the mutation, which was not found in 10,758 control chromosomes.
In affected members of a large 4-generation pedigree with auriculocondylar syndrome (ARCND2A; 614669), originally reported by Storm et al. (2005) (family 1), Rieder et al. (2012) identified heterozygosity for a c.1862G-A transition (c.1862G-A, NM_000933.3) in the PLCB4 gene, resulting in an arg621-to-his (R621H) substitution at a highly conserved residue in the catalytic site. The mutation segregated with disease in the family and was not found in 10,758 control chromosomes.
In a boy from Oman with ARCND, Gordon et al. (2013) identified heterozygosity for a de novo R621H mutation in the PLCB4 gene. His unaffected parents and brother did not carry the mutation.
In 4 affected members of a 3-generation Egyptian family with ARCND, Nabil et al. (2020) identified heterozygosity for the R621H substitution in the PLCB4 gene that segregated fully with disease in the pedigree. The family displayed striking intrafamilial variability: affected individuals included a 6-year-old girl and her 17-year-old male cousin, who had typical question mark ears (QMEs), prominent cheeks, and microretrognathia, with temporomandibular joint (TMJ) abnormalities and ankylosis, whereas their fathers were more mildly affected, without TMJ abnormalities, and their deceased paternal grandmother was said to have had isolated QMEs.
Vegas et al. (2022) reported a boy (family 8, patient 9) with unilateral QME, microretrognathia, microstomia, with delayed motor and speech milestones, who was heterozygous for the R621H mutation in the PLCB4 gene. His mother (patient 10), who had bilateral QMEs and dysplastic condyles on craniofacial CT scan, was also heterozygous for the R621H variant, as was his maternal grandmother (patient 11), in whom clinical examination was normal. Thus, this family represented incomplete penetrance and variable expressivity. An unrelated 15-year-old Algerian girl (patient 19) with bilateral QME, retrognathia, delayed puberty, intellectual deficiency, and motor dyspraxia was also heterozygous for the R621H substitution, which in her had arisen de novo.
In the male proband of a 4-generation family with auriculocondylar syndrome (ARCND2A; 614669), Rieder et al. (2012) identified heterozygosity for a c.1861C-T transition (c.1861C-T, NM_000933.3) in the PLCB4 gene, resulting in an arg621-to-cys (R621C) substitution at a highly conserved residue in the catalytic site. The proband had micrognathia, cleft palate, glossoptosis, and a constriction between the helix and lobule of his left ear. Variable expressivity and incomplete penetrance were exhibited in this family, as the proband's father, who had only asymmetric ear lobes, was also heterozygous for the mutation, and there were 4 other paternal relatives who displayed only ear malformations with or without micrognathia.
In a boy with ARCND, who was originally reported by Gerkes et al. (2008), Gordon et al. (2013) identified heterozygosity for a de novo R621C mutation in the PLCB4 gene. His unaffected parents, who had normal orthopantograms, did not carry the mutation.
Vegas et al. (2022) reported 2 unrelated male and female probands (patients 8 and 18) with ARCND and heterozygosity for the R621C mutation in the PLCB4 gene. In patient 8 the mutation was de novo; parental mutation status was not reported for patient 18, born of healthy consanguineous parents from North Africa. Both patients had bilateral question mark ears and micrognathia; patient 8 also had swallowing difficulties and a hypomobile tongue. Both probands snored during sleep, and sleep studies performed in patient 18 showed mixed obstructive and central apnea. Patient 18 also had dental agenesis and misalignment. CT scans revealed mandibular and condylar dysplasia, and both patients underwent mandibular distraction procedures.
In affected members of a large 4-generation pedigree with auriculocondylar syndrome (ARCND2A; 614669), originally reported by Storm et al. (2005) (family 2), Rieder et al. (2012) identified heterozygosity for a c.1948A-C transversion (c.1948A-C, NM_000933.3) in the PLCB4 gene, resulting in an asn650-to-his (N650H) substitution at a highly conserved residue in the catalytic site. The mutation segregated with disease in the family and was not found in 10,758 control chromosomes.
In a girl from the UK with classic features of auriculocondylar syndrome (ARCND2A; 614669), who was previously published in Figures 62c and 66a of Hunter et al. (2009), Gordon et al. (2013) identified heterozygosity for a c.1862G-T transversion in the PLCB4 gene, resulting in an arg621-to-leu (R621L) substitution within the Y subdomain of the catalytic domain. The patient had severe micrognathia, large cheeks, microstomia, and overfolded helices with a large postauricular tag on her left ear. She inherited the mutation from her father, who had a small low-set right ear with a dysplastic and overfolded helix without anomaly at the lobe-helix junction, and shorter than normal mandibular rami with a flattened head of the right condyle on orthopantogram.
In a father and daughter with auriculocondylar syndrome (ARCND2A; 614669), who were originally reported as having isolated question mark ears by Shkalim et al. (2008), Gordon et al. (2013) identified heterozygosity for a c.1073A-T transversion in the PLCB4 gene, resulting in a glu358-to-val (E258V) substitution within the X subdomain of the catalytic domain. Gordon et al. (2013) observed that the lower jaws of both patients were mildly dysplastic, and that some degree of mandibular dysplasia may have been present in the paternal grandfather; however, permission was not granted to publish photographs, and the authors were unable to assess x-rays or mandibular scans in this family. The mutation was also present in a clinically unaffected daughter, suggesting incomplete penetrance.
In a female patient with auriculocondylar syndrome (ARCND2A; 614669), who was originally described by Stuffken and Tuinzing (2008), Gordon et al. (2013) identified heterozygosity for a c.1078G-A transition in the PLCB4 gene, resulting in an asp360-to-asn (D360N) substitution. The patient, who was previously diagnosed as having dysgnathia complex, presented the core features of ARCND, including a crease between the earlobe and helix, micrognathia, and dysplastic temporomandibular joints on radiography. Parental data were unavailable.
In a male patient with auriculocondylar syndrome (ARCND2A; 614669), who was originally reported by Greig et al. (2012), Gordon et al. (2013) identified heterozygosity for a c.1079A-T transversion in the PLCB4 gene, resulting in an asp360-to-val (D360V) substitution. The patient had a unilateral mild question mark ear deformity, with a subtle notch at the junction between the lobe and helix; CT scan revealed severe bilateral condylar hypoplasia and dysmorphic ramus/condyle units. An initial sleep study indicated predominantly obstructive apnea, but in a sleep study performed after distraction surgery, the majority of apneic episodes appeared to be central in origin and generally occurred during rapid eye movement sleep or after arousals, although they were not deemed pathologic.
In a boy with auriculocondylar syndrome and macropenis (ARCND2B; 620458), born to second-cousin parents of Indian origin, Gordon et al. (2013) identified homozygosity for a 4,997-bp deletion (chr20:9,388,282-9,393,278; GRCh37), causing a frameshift predicted to result in a premature termination codon. His clinically unaffected parents were heterozygous for the deletion.
In 2 Japanese brothers with auriculocondylar syndrome, gastroesophageal reflux, chronic constipation, and macropenis (ARCND2B; 620458), Kido et al. (2013) identified compound heterozygosity for splice site mutations in the PLCB4 gene: a c.854-1G-A transition (c.854-1G-A, NM_000933.3) in intron 12, and a c.1238+1G-C transversion in intron 15 (600810.0012). Both mutations were predicted to disrupt the splice site, and neither was found in the dbSNP137 or EVS databases. Their unaffected parents were each heterozygous for 1 of the mutations, supporting a loss-of-function, but not dominant-negative, effect.
For a discussion of the c.1238+1G-C transversion (c.1238+1G-C, NM_000933.3) in intron 15 of the PLCB4 gene, predicted to disrupt the splice site, that was found in compound heterozygous state in 2 Japanese brothers with auriculocondylar syndrome, gastroesophageal reflux, chronic constipation, and macropenis (ARCND2B; 620458) by Kido et al. (2013), see 600810.0011.
In a 6-year-old girl with auriculocondylar syndrome, gastroesophageal reflux, chronic constipation, and clitoral hypertrophy (ARCND2B; 620458), Leoni et al. (2016) identified homozygosity for a 1-bp deletion (c.624delG, NM_000933.3) in exon 10 of the PLCB4 gene, causing a frameshift predicted to result in a premature termination codon (Lys208AsnfsTer5). Her unaffected parents were both heterozygous for the deletion, which was not found in the dbSNP141, EVS, or ExAC databases.
In a Brazilian girl (patient 1) with auriculocondylar syndrome (ARCND2A; 614669), originally described by Kokitsu-Nakata et al. (2012), Romanelli Tavares et al. (2017) identified heterozygosity for a c.1072G-C transversion (c.1072G-C, NM_000933.3) in exon 12 of the PLCB4 gene, resulting in a glu358-to-gln (E358Q) substitution. Her mother did not carry the mutation, which was also not found in the 1000 Genomes, NHLBI ESP, ExAC, dbSNP144, or ABraOM databases; DNA was not available from the father.
In the proband (patient 2) from a 3-generation family with auriculocondylar syndrome (ARCND2A; 614669), originally described by Kokitsu-Nakata et al. (2012), Romanelli Tavares et al. (2017) identified heterozygosity for a c.983A-G transition (c.983A-G, NM_000933.3) in exon 11 of the PLCB4 gene, resulting in a his328-to-arg (H328R) substitution. The mutation segregated fully with disease in the pedigree, and was not found in the 1000 Genomes, NHLBI ESP, ExAC, dbSNP144, or ABraOM databases.
In a 4.5-year-old Turkish girl (patient 23) with auriculocondylar syndrome, severe mixed sleep apnea, feeding difficulties, and developmental delay (ARCND2B; 620458), Vegas et al. (2022) identified homozygosity for a 1-bp duplication (c.1620dup, NM_000933.4) in the PLCB4 gene, causing a frameshift predicted to result in a premature termination codon (Thr541HisfsTer5). Her unaffected parents were heterozygous for the duplication.
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