Alternative titles; symbols
HGNC Approved Gene Symbol: TMEM67
SNOMEDCT: 723999009;
Cytogenetic location: 8q22.1 Genomic coordinates (GRCh38): 8:93,754,844-93,832,653 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.1 | ?RHYNS syndrome | 602152 | Autosomal recessive | 3 |
| {Bardet-Biedl syndrome 14, modifier of} | 615991 | Autosomal recessive | 3 | |
| COACH syndrome 1 | 216360 | Autosomal recessive | 3 | |
| Joubert syndrome 6 | 610688 | Autosomal recessive | 3 | |
| Meckel syndrome 3 | 607361 | Autosomal recessive | 3 | |
| Nephronophthisis 11 | 613550 | Autosomal recessive | 3 |
Smith et al. (2006) refined mapping of a Meckel syndrome locus (MKS3; 607361) to a 12.67-Mb interval on chromosome 8q21.13-q22.1, which is syntenic to the Wpk locus in rat. Positional cloning of the Wpk gene suggested an MKS3 candidate gene, TMEM67 (transmembrane protein-67). The human TMEM67 gene encodes a deduced 995-amino acid protein, which the authors called meckelin, with a calculated unglycosylated mass of 108 kD. Human and rat meckelin share 84% identity. Meckelin was predicted to contain a signal peptide, at least 2 cysteine-rich repeats, and a 490-residue extracellular region with 4 N-linked glycosylated sites, followed by 7 transmembrane domains and a 30-residue cytoplasmic tail. RNA blotting identified a primary transcript of 4.0 kb and a weaker product of 4.5 kb expressed in all adult and fetal human tissues tested. Real-time quantitative PCR analysis of human embryonic tissues detected highest expression in spinal cord and moderate levels in adrenal tissue, brain, and kidney.
Using in situ hybridization with human embryos, Dawe et al. (2007) found that meckelin was expressed in kidney, liver, retina, hindbrain, developing sphenoid bone, and the brain midline. Intense expression was also detected in cartilage of developing limbs, particularly in the digits. Immunohistochemical analysis of 18- to 20-week-old human fetal kidneys detected moderate to high expression of meckelin and MKS1 (609883) at the proximal renal tubule epithelia, but not at glomeruli. In liver, these proteins were also expressed at the biliary epithelium of larger bile ducts, but not in hepatocytes. In HEK293 cells, meckelin was expressed at the cell border and colocalized with alpha-tubulin (see 602529) at primary cilia. Western blot analysis detected meckelin at an apparent molecular mass of 120 kD.
By sequence analysis, Smith et al. (2006) mapped the TMEM67 gene to chromosome 8q21.13-q22.1.
Using RNA interference, Dawe et al. (2007) found that knockdown of either Mks1 or Mks3 in mouse inner medullary IMCD-3 cells blocked centriole migration to the apical membrane and formation of the primary cilium. Coimmunoprecipitation experiments showed that wildtype Mks1 and Mks3 interacted, and knockdown of either Mks1 or Mks3 in IMCD-3 cells decreased the formation of highly branched structures and tubules in 3-dimensional cultures. Dawe et al. (2007) concluded that MKS1 and MKS3 have roles in ciliogenesis and renal tubulogenesis.
Tammachote et al. (2009) showed that kidney tissue and cells from MKS1 (249000) and MKS3 patients showed defects in centrosome and cilia number, including multiciliated respiratory-like epithelia, and longer cilia. Stable shRNA knockdown of Mks1 and Mks3 in IMCD-3 cells induced multiciliated and multicentrosomal phenotypes. MKS1 and MKS3 functions are required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. Tammachote et al. (2009) concluded that MKS1 and MKS3 are ciliopathies, with new cilia-related eye and sperm phenotypes defined.
Williams et al. (2011) showed that the conserved proteins Mks1, Mksr1 (B9D1; 614144), Mksr2 (B9D2; 611951), Tmem67, Rpgrip1l (610937), Cc2d2a (612013), Nphp1 (607100), and Nphp4 (607215) functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins.
By yeast 2-hybrid and immunoprecipitation analyses, Adams et al. (2012) found that the C-terminal cytoplasmic tail of meckelin interacted with filamin A (FLNA; 300017). Loss of filamin A or meckelin in immortalized fibroblasts from patients with null mutations in the genes or by small interfering RNA in mouse IMCD3 cells resulted in similar cellular phenotypes, including abnormal basal body positioning and ciliogenesis, aberrant remodeling of the actin cytoskeleton, deregulation of RHOA (165390) activity, and hyperactivation of canonical Wnt (see 606359) signaling. Adams et al. (2012) concluded that the meckelin-filamin A signaling axis is a key regulator of ciliogenesis and normal Wnt signaling.
Meckel Syndrome 3
In 5 consanguineous families with Meckel syndrome linked to chromosome 8q21.13-q22.1 (MKS3; 607361), Smith et al. (2006) detected 5 different homozygous mutations in the TMEM67 gene (609884.0001-609884.0005). The mutations consisted of 2 frameshift deletions, 2 splicing mutations, and a nonconservative missense change. The mutations were not found in over 120 ethnically matched normal control chromosomes.
Consugar et al. (2007) identified 7 novel pathogenic mutations in the TMEM67 gene (see, e.g., 609884.0011) in 5 of 17 families with a clinical diagnosis of Meckel syndrome.
Joubert Syndrome 6
Joubert syndrome (JBTS; see 213300) is an autosomal recessive disorder characterized by cerebellar vermis hypoplasia associated with hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The association of retinal dystrophy and renal anomalies defines a subtype of JBTS. Occipital encephalocele and polydactyly have occasionally been reported in patients with JBTS. These features are also found in Meckel-Gruber syndrome. The phenotypic overlap between JBTS and Meckel-Gruber syndrome is supported by the central nervous system malformations seen in the Wpk rat model of Meckel-Gruber syndrome, which includes agenesis of the corpus callosum and hydrocephalus but not exencephaly. The missense mutation, P394L, seen in the rat Mks3 gene is presumably a hypomorphic allele because of the mild phenotype and viability of the Wpk rat (Smith et al., 2006). While sequencing MKS1 (609883) and MKS3 genes in 31 unrelated fetuses presenting a cerebrorenodigital syndrome, which was designated 'Meckel-like' because of the absence of at least 1 of the MKS diagnostic criteria, Baala et al. (2007) identified MKS3 mutations in a family with 2 sibs. The pregnancies were terminated at 30 weeks' and 28 weeks' gestation, respectively, because of abnormal posterior fossae and hyperechogenic, enlarged kidneys detected by ultrasound. Kidney pathology in both fetuses showed liver bile duct proliferation and microcysts mainly in the medulla. Abnormalities in the brainstem resembling those of Joubert syndrome were described. The 2 sibs were found to be compound heterozygous for 2 mutations in the MKS3 gene: a missense mutation, Y513C, inherited from the father (609884.0006) and an insertion/deletion mutation inherited from the mother (609884.0007). Despite the absence of neurologic symptoms required for postnatal diagnosis in these sibs, Baala et al. (2007) questioned what MKS gene mutations could be found in patients with typical JBTS and sequenced 22 patients who had no deletion of the NPHP1 gene (607100). Sequence analysis revealed mutations in 3 patients. Studies identified the MKS3 gene as mutant in a sixth form of Joubert syndrome (JBTS6; 610688).
Otto et al. (2009) identified TMEM67 mutations (see, e.g., 609884.0011; 609884.0013; 609884.0019; 609884.0021-609884.0023) in 4 (3.3%) of 120 unrelated probands with Joubert syndrome. In 1 family another member was also affected. All 5 patients had ataxia, hypotonia or psychomotor retardation or showed cerebellar vermis hypo- or aplasia. All developed end-stage renal disease between 8 and 15 years of age, and 4 had hepatic fibrosis. Four also had ocular involvement, including blindness, retinal degeneration, or retinal coloboma.
Bardet-Biedl Syndrome
The identification of mutations in the MKS1 gene (609883) in patients with clinical diagnoses of Bardet-Biedl syndrome (BBS; 209900) led Leitch et al. (2008) to investigate other Meckel syndrome genes as contributors to the BBS phenotype. While they did not find families with 2 pathogenic alleles in the MKS3 gene, they did find 2 families harboring potentially pathogenic heterozygous alleles. In one of these families a splice-site mutation in MKS3 was found with homozygosity for a BBS9 mutation (607968). An individual from the second family carried a complex allele encoding a protein with 2 in cis changes. One of the changes was predicted to be benign; the second, S320C (609884.0012), was predicted to be pathogenic. This patient also carried a homozygous truncating mutation in CEP290 (610142.0013).
COACH Syndrome 1
COACH syndrome-1 (COACH1; 216360) is an autosomal recessive disorder originally described as including cerebellar vermis hypoplasia, oligophrenia, ataxia, ocular coloboma, and congenital hepatic fibrosis (Verloes and Lambotte, 1989). The clinical features overlap with those observed in Joubert and Meckel syndromes. In 8 (57%) of 14 families diagnosed with COACH syndrome, defined as Joubert syndrome with congenital liver fibrosis, Brancati et al. (2009) identified compound heterozygous mutations in the TMEM67 gene (see, e.g., 609884.0013-609885.0016). One of the families included the original family reported by Verloes and Lambotte (1989) (609884.0013 and 609884.0014). The phenotype in all patients was consistent with Joubert syndrome with congenital hepatic fibrosis, indicating that COACH syndrome can be considered a subtype of Joubert syndrome. The clinical variability of the disorder, relating to the extent and severity of liver and neurologic dysfunction as well as to the presence or absence of ocular and renal findings, was hypothesized to be due to genetic modifiers, similar to other ciliopathies, including Bardet-Biedl syndrome (BBS; 209900).
Doherty et al. (2010) identified mutations in the TMEM67 gene in 19 (83%) of 23 families with COACH syndrome, defined as Joubert syndrome with liver disease. In contrast, TMEM67 mutations were only found in 2 (1%) of 209 families with Joubert syndrome without liver involvement. The findings further supported the concept that COACH syndrome is a form of Joubert syndrome with hepatic fibrosis. The proposed ciliary function for TMEM67 supported a unifying underlying pathophysiology for liver disease in these disorders.
In a 20-year-old Korean man with COACH syndrome, Lee et al. (2017) identified compound heterozygous mutations in the TMEM67 gene (G132A, 609884.0027 and c.2758delT, 609884.0028). Transfection experiments in HEK293T cells showed that the c.2758delT mutation resulted in decreased stability and increased turnover of the protein, and the G132A mutation resulted in decreased mRNA expression, compared to wildtype. In TMEM67 knockdown zebrafish with a hydrocephalus phenotype, injection with mutant morpholinos containing the G132A or c.2758delT mutation did not rescue the phenotype. Injection with the 2 mutant morpholinos in the TMEM67 knockdown zebrafish also did not rescue wnt signaling defects, as evidenced by suppressed axin2 (604025) mRNA.
Nephronophthisis 11
In patients with nephronophthisis and hepatic fibrosis (NPHP11; 613550), Otto et al. (2009) identified homozygous or compound heterozygous missense mutations in the TMEM67 gene (see, e.g., 609884.0018-609884.0021). Mutations in the TMEM67 gene were not found in 105 NPHP patients without liver fibrosis, suggesting that liver fibrosis is a specific feature of TMEM67 mutations. Otto et al. (2009) concluded that mutations in TMEM67 can cause NPHP in patients with additional liver fibrosis but without neurologic involvement and with normal brain imaging, and that NPHP11, MKS3, and JBTS6 represent a spectrum of allelic disorders.
RHYNS Syndrome
In a 38-year-old Italian man with RHYNS syndrome (RHYNS; 602152), Brancati et al. (2018) identified compound heterozygosity for a nonsense mutation (R208X; 609884.0011) and a missense mutation (D430G; 609884.0026) in the TMEM67 gene. The mutations segregated with disease in the family.
Otto et al. (2009) found homozygosity or compound heterozygosity for missense mutations in the TMEM67 gene (609884.0018-609884.0021) in patients with NPHP11 and hepatic fibrosis. All patients with NPHP and hepatic fibrosis and no brain anomaly carried a missense mutation affecting either amino acid C615 or G821. Thus, Otto et al. (2009) suggested that some hypomorphic mutations of TMEM67 do not lead to any neurologic impairment. Four additional patients with a more severe phenotype of Joubert syndrome-6 also had homozygous or compound heterozygous mutations (see, e.g., 609884.0011; 609884.0013; 609884.0019; 609884.0021-609884.0023). None of the patients with JBTS6 had truncating mutations on both alleles; all had at least 1 missense allele. Finally, the liver seems to be affected in most of the patients with TMEM67 mutations independently of the neurologic involvement, suggesting that liver disease is a specific feature resulting from TMEM67 mutations.
In the Wistar polycystic kidneys (Wpk) rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum, and hydrocephalus, Smith et al. (2006) refined the mapping of the Wpk locus and identified a missense mutation in the rat Tmem67 gene that was not present in the parental Wistar strain.
In the Wpk rat model of MKS3, Tammachote et al. (2009) reported functional defects of the connecting cilium in the eye that resulted in lack of formation of the outer segment, whereas infertile Wpk males developed spermatids with very short flagella that did not extend beyond the cell body. In Wpk renal collecting duct cysts, cilia were generally longer than normal, with additional evidence of cells with multiple primary cilia and centrosome overduplication.
Garcia-Gonzalo et al. (2011) found that Tmem67-null mice survived to birth without overt morphologic abnormalities, but died soon after. By embryonic day 18.5, Tmem67-null embryonic kidneys had developed cysts, and kidney tubules had fewer cilia than controls. Tmem67-null embryonic fibroblasts did not have ciliary defects, suggesting that Tmem67 has tissue-specific roles in ciliogenesis. Garcia-Gonzalo et al. (2011) also demonstrated that Tmem67 interacts with Tctn1 (609863) and Tctn2 (613846) and other proteins in a large complex localized to the transition zone between the ciliary axoneme and the basal body.
Adams et al. (2012) found that knockdown of Mks3 or the Flna ortholog in zebrafish resulted in similar phenotypes, including brain and body axis defects, cardiac edema, and otic placode and eye defects. Combined low doses of both Mks3 and Flna morpholinos increased both the incidence and severity of developmental defects. An Flna-null mouse strain showed similar defects. At embryonic day 13.5, male Flna hemizygous embryos were highly dysmorphic, with extensive disruption of ventricular zone of the neocortex and severe periventricular heterotopia. Basal body position was disrupted and neuroepithelial layer showed impaired ciliogenesis.
Abdelhamed et al. (2013) found that knockdown of Tmem67 in mice recapitulated the phenotypic variability of neurologic features seen in human ciliopathies. Two main phenotypic groups were recognized. Incipient congenic mice (F6 to F10) showed MKS-like features with variable neurologic abnormalities, including exencephaly and frontal/occipital encephalocele associated with the loss of primary cilia, diminished Shh signaling, and dorsalization of the caudal neural tube. These mutant mice also showed highly deregulated canonical Wnt/beta-catenin (CTNNB1; 116806) signaling associated with hyperactive DVL1 (601365) localized to the basal body: DVL1 is the downstream signaling modulator of Wnt pathways. Conversely, fully congenic mice (F greater than 10) had less variable neurodevelopmental features that were characteristic of JBTS, including cerebellar hypoplasia consistent with the molar tooth sign on imaging, and retention of abnormal bulbous cilia associated with neural tube ventralization. These mutant mice had low levels of deregulated canonical Wnt signaling associated with the loss of DVL1 localization to the basal body. Abdelhamed et al. (2013) suggested that modifier alleles likely determine the variation between MKS and JBTS caused by TMEM67 mutations.
In an individual with Meckel syndrome type 3 (MKS3; 607361) from Oman, Smith et al. (2006) found a homozygous 2-bp deletion in exon 3 of the MKS3 gene, 383_384delAC, causing a frameshift beginning at his128 with premature stop at residue 140 (H128fsTer140). Each of the first-cousin parents was heterozygous for the mutation. The affected individual had occipital encephalocele, Dandy-Walker cysts, renal cystic dysplasia, hepatic developmental defects, and left-hand postaxial polydactyly.
In a Pakistani family with Meckel syndrome type 3 (MKS3; 607361), Smith et al. (2006) found that 2 affected sibs carried a homozygous 1-bp deletion (647delA) in exon 6 of the MKS3 gene. The deletion caused a frameshift beginning at glu216 of the protein, with premature termination at residue 221. The sibs had occipital encephalocele, renal cystic dysplasia, hepatic developmental defects, and midline cleft palate.
By immunohistochemical analysis, Dawe et al. (2007) found complete lack of meckelin expression in kidney from a patient with the 647delA mutation.
In a Pakistani family with Meckel syndrome type 3 (MKS3; 607361), Smith et al. (2006) found that a child with Meckel syndrome carried a homozygous splice site mutation, IVS8-2A-G, in the MKS3 gene. The child had occipital encephalocele, renal cystic dysplasia, and hepatic developmental defects.
In a Pakistani patient with Meckel syndrome type 3 (MKS3; 607361), Smith et al. (2006) found a homozygous 1127A-C transversion in exon 11 of the MKS3 gene causing a missense protein change, Q376P. The patient had occipital encephalocele, renal cystic dysplasia, hepatic developmental defects, midline cleft palate, and epididymal cysts.
By immunohistochemical analysis, Dawe et al. (2007) found that the Q376P substitution in the N-terminal extracellular domain of meckelin resulted in lack of meckelin at the cell surface due to accumulation of the mutant protein in the endoplasmic reticulum.
In 2 Pakistani cases of Meckel syndrome type 3 (MKS3; 607361) in individuals related as double first cousins, Smith et al. (2006) found that the disorder was related to a homozygous splice site mutation in intron 15 of the MKS3 gene: IVS15+1G-A. One patient had occipital encephalocele, renal cystic dysplasia, and hepatic developmental defects; the other had the same 3 features as well as bilateral postaxial polydactyly.
Joubert Syndrome 6
In 2 sibs derived from pregnancies terminated at 30 weeks' and 28 weeks' gestation, respectively, because of abnormal posterior fossae and hyperechogenic, enlarged kidneys detected by ultrasound, Baala et al. (2007) found compound heterozygosity for 2 mutations in the MKS3 gene. A missense mutation in exon 15, tyr513 to cys (Y513C), was inherited from the father; a complex indel mutation (13-bp deletion encompassing the exon 22/intron 22 boundary replaced by 2 bp) was inherited from the mother. This 2315_2323+4del13insGG mutation (609884.0007) removed the donor splice site. Strong suspicion of Joubert syndrome in this family prompted a search for MKS3 mutations in patients with a typical form of the disorder and led to the establishment of a sixth locus for Joubert syndrome (JBTS6; 610688).
COACH Syndrome 1
Doherty et al. (2010) identified the Y513C mutation in compound heterozygosity with another pathogenic TMEM67 mutation (see, e.g., I833T, 609884.0013) in 2 families with COACH syndrome-1 (COACH1; 216360), defined as Joubert syndrome with hepatic involvement.
For discussion of the complex indel mutation in the TMEM67 gene (13-bp deletion encompassing the exon 22/intron 22 boundary replaced by 2 bp) that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Baala et al. (2007), see 609884.0006.
In a 14-year-old Algerian girl, the child of consanguineous parents, with the molar tooth sign and superior vermian dysplasia (JBTS6; 610688), Baala et al. (2007) found homozygous MKS3 mutation near the donor splice site of intron 23 (IVS23+5G-C). Both parents and a healthy sister were heterozygous for the mutation. Sequencing of RNA transcript confirmed exon skipping from exons 22 to 24. This in-frame deletion predicted a protein lacking amino acids 775 to 813, which compose most of the putative coiled-coil domain of the protein. This patient had been reported by Romano et al. (2006).
Baala et al. (2007) demonstrated compound heterozygosity for mutations in the MKS3 gene in a 7-year-old girl with a mild form of Joubert syndrome (JBTS6; 610688). The patient had been reported by Romano et al. (2006). Three MKS3 variations were found: on the maternal allele, a donor splice site mutation in intron 6 (IVS6+2T-G), and on the paternal allele, a missense mutation located in exon 16 (G545E; 609884.0010) and a mutation located at the last base of exon 21 (2341G-A; 609884.0010). Either of the mutations from the father could be deleterious.
For discussion of the in cis gly545-to-glu (G545E) and 2431G-A mutations in the TMEM67 gene that were found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Baala et al. (2007), see 609884.0009.
Meckel Syndrome 3
In affected fetuses from 3 unrelated families with Meckel syndrome type 3 (MKS3; 607361), Consugar et al. (2007) identified a heterozygous 622A-T transversion in exon 6 of the TMEM67 gene, resulting in an arg208-to-ter (R208X) substitution. All fetuses were compound heterozygous for R208X and another pathogenic mutation in the TMEM67 gene.
Joubert Syndrome 6
In a German patient with Joubert syndrome-6 (JBTS6; 610688), Otto et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: R208X and I833T (609884.0013). The patient had end-stage renal failure at age 15, hepatic fibrosis, mental retardation, and cerebellar vermis atrophy. No ocular involvement was observed.
RHYNS Syndrome
In a 38-year-old Italian man with RHYNS syndrome (RHYNS; 602152), originally reported by Di Rocco et al. (1997), Brancati et al. (2018) identified compound heterozygosity for the R208X mutation (c.622A-T, NM_153704.5) in the TMEM67 gene, and a c.1289A-G transition in exon 13, resulting in an asp430-to-gly (D430G; 609884.0026) substitution. His unaffected father and 2 unaffected brothers were heterozygous for the nonsense mutation, and his unaffected mother was heterozygous for the missense mutation. The D430G missense mutation was not found in the 1000 Genomes Project, ExAC, or gnomAD databases, whereas the nonsense mutation was present at very low frequency in the gnomAD database (49 of 277,178 alleles). Minigene assay using the pSPL3 vector system revealed absence of exon 13 after transfection with the D430G mutant; the authors suggested that the c.1289A-G mutation might result in exon 13 skipping, causing a frameshift and premature termination (Asp430SerfsTer9).
In an 11-year-old female patient with Bardet-Biedl syndrome (see BBS14, 615991) Leitch et al. (2008) found heterozygosity for a complex mutation in the TMEM67 gene coding for a protein with 2 in cis changes, in addition to homozygosity for a truncating mutation of the CEP290 gene (610142.0013). One of the substitutions in the TMEM67 gene was predicted computationally to be benign, while the other, ser320 to cys (S320C), occurred at a highly conserved residue and was predicted to be pathogenic. The S320C mutation resulted in severe gastrulation movement defects in zebrafish embryos.
COACH Syndrome 1
In 2 sibs originally reported by Verloes and Lambotte (1989) as having COACH syndrome (COACH1; 216360), Brancati et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: a 2498T-C transition in exon 24, resulting in an ile833-to-thr (I833T) substitution, and a splice site mutation in intron 24 (2556+1G-T; 609884.0014). An unrelated patient from Croatia was compound heterozygous for I833T and another splice site mutation in intron 2 (312+5G-A; 609884.0015). The phenotype in all patients was consistent with Joubert syndrome (JBTS6; 610688) with congenital hepatic fibrosis, indicating that COACH syndrome is a subtype of Joubert syndrome.
Doherty et al. (2010) identified the I833T mutation in compound heterozygosity with another pathogenic TMEM67 mutation (see, e.g., Y513C; 609884.0006) in 4 unrelated patients with COACH syndrome, which the authors defined as Joubert syndrome with liver involvement.
Joubert Syndrome 6
In a patient diagnosed with Joubert syndrome, Otto et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: I833T and R208X (609884.0011). The patient had end-stage renal failure at age 16, liver fibrosis, mental retardation, and cerebellar vermis aplasia. Ocular involvement was not observed.
In a German girl with Joubert syndrome, Dafinger et al. (2011) identified compound heterozygosity for 2 mutations in the TMEM67 gene: I833T and pro358 to leu (P358L; 609884.0024). She also had a heterozygous 12-bp deletion in the KIF7 gene (3986del12; 611254.0008). The patient had mental retardation, molar tooth sign on brain MRI, ataxia, hypertelorism, low-set ears, coloboma, and elevated liver enzymes.
For discussion of the splice site mutation in intron 24 of the TMEM67 gene (2556+1G-T) that was found in compound heterozygous state in patients with COACH syndrome (COACH1; 216360) by Brancati et al. (2009), see 609884.0013.
For discussion of the splice site mutation in intron 2 of the TMEM67 gene (312+5G-A) that was found in compound heterozygous state in patients with COACH syndrome (COACH1; 216360) by Brancati et al. (2009), see 609884.0013.
In 2 Italian brothers with COACH syndrome (COACH1; 216360) reported by Gentile et al. (1996), Brancati et al. (2009) identified compound heterozygosity for 2 mutations in the TMEM67 gene: a 1769T-C transition in exon 17, resulting in a phe590-to-ser (F590S) substitution, and a splice site mutation in intron 19 (1961-2A-C; 609884.0017).
For discussion of the splice mutation in intron 19 of the TMEM67 gene (1961-2A-C) that was found in compound heterozygous state in patients with COACH syndrome (COACH1; 216360) by Brancati et al. (2009), see 609884.0016.
In 3 sibs, born of consanguineous Turkish parents, with nephronophthisis and hepatic fibrosis (NPHP11; 613550), Otto et al. (2009) identified a homozygous 2461G-A transition in exon 24 of the TMEM67 gene, resulting in a gly821-to-ser (G821S) substitution in a highly conserved residue. The mutation was not found in 188 controls or in 147 ethnically matched controls. The patients developed end-stage renal disease between ages 9 and 14 years and had no neurologic abnormalities.
Nephronophthisis 11
In a Turkish patient, born of consanguineous parents, with nephronophthisis-11 and hepatic fibrosis (NPHP11; 613550), Otto et al. (2009) identified a homozygous 1843T-C transition in exon 18 of the TMEM67 gene, resulting in a cys615-to-arg (C615R) substitution in a highly conserved residue. A German patient was also found to be homozygous for the mutation, and haplotype analysis indicated a common founder. The Turkish patient had end-stage renal failure at age 6, liver fibrosis, retinal degeneration, and mild cortical atrophy. The German patient had end-stage renal failure at age 6, liver fibrosis, Ehlers-Danlos syndrome, and no ocular or neurologic involvement. Another German patient with NPHP, liver fibrosis, strabismus, nystagmus, and mild 'statomotoric' retardation was found to be compound heterozygous for C615R and an 869G-T transversion in exon 8, resulting in a trp290-to-leu (W290L; 609884.0020) substitution.
Joubert Syndrome 6
Otto et al. (2009) reported a patient with Joubert syndrome-6 (JBTS6; 610688) who was compound heterozygous for C615R and a 755T-C transition in exon 8 of the TMEM67 gene, resulting in a met252-to-thr (M252T; 609884.0023) substitution. The patient had end-stage renal failure at age 14, hepatic fibrosis, nystagmus, oculomotor apraxia, chorioretinal coloboma, ataxia, and psychomotor retardation.
For discussion of the trp290-to-leu (W290L) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with nephronophthisis-11 (NPHP11; 613550) by Otto et al. (2009), see 609884.0019.
In a German patient with nephronophthisis-11 and hepatic fibrosis (NPHP11; 613550), Otto et al. (2009) identified a homozygous 2461G-C transversion in exon 24 of the TMEM67 gene, resulting in a gly821-to-arg (G821R) substitution. The patient developed end-stage renal failure at age 10 years, and also had anisocoria and psychomotor retardation, but normal brain MRI findings. An unrelated German patient with a more severe phenotype, consistent with Joubert syndrome-6 (JBTS6; 610688), was compound heterozygous for G821R and a 130C-T transition in exon 1, resulting in a gln44-to-ter (Q44X; 609884.0022) substitution. The patient with Joubert syndrome had end-stage renal failure at age 12, retinal degeneration, chorioretinal coloboma, ataxia, and cerebellar vermis aplasia. Liver involvement was not reported. Haplotype analysis of both patients indicated a common origin for the G821R mutation.
For discussion of the gln44-to-ter (Q44X) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Otto et al. (2009), see 609884.0021.
For discussion of the met252-to-thr (M252T) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Otto et al. (2009), see 609884.0019.
For discussion of the pro358-to-leu (P358L) mutation in the TMEM67 gene that was found in compound heterozygous state in a patient with Joubert syndrome-6 (JBTS6; 610688) by Dafinger et al. (2011), see 609884.0013.
In a patient from a consanguineous family who presented with Meckel syndrome type 3 (MKS3; 607361) and cerebellar heterotopia, Adams et al. (2012) identified a homozygous 3-bp deletion, c.2754_2756delCTT, resulting in an in-frame deletion of phe919 (919delF) in the C-terminal cytoplasmic region of meckelin. The deletion abrogated the interaction of meckelin with filamin A (FLNA; 300017), resulting in aberrant hyperactivation of canonical Wnt signaling in patient fibroblasts compared with controls.
For discussion of the c.1289A-G transition (c.1289A-G, NM_153704.5) in exon 13 of the TMEM67 gene, resulting in an asp430-to-gly (D430G) substitution, that was found in compound heterozygous state in a 38-year-old Italian man with RHYNS syndrome (602152) by Brancati et al. (2018), see 609884.0011.
In a 20-year-old Korean man with COACH syndrome-1 (COACH1; 216360), Lee et al. (2017) identified compound heterozygous mutations in the TMEM67 gene: a c.395G-C transversion (c.395G-C, NM_153704.5) in exon 3, resulting in a gly132-to-ala (G132A) substitution in the cysteine-rich region, and a 1-bp deletion (c.2758delT; 609884.0028) in exon 26, resulting in a frameshift and premature termination (Tyr920ThrfsTer40). Both mutations occurred at highly conserved residues. The mutations were found by sequencing of the TMEM67 gene. The father was heterozygous for the mutation, but the mother was not tested. Transfection experiments in HEK293T cells showed that the c.2758delT mutation resulted in decreased stability and increased turnover of the protein, and the G132A mutation resulted in decreased mRNA expression, compared to wildtype. In TMEM67 Lee et al. (2017) also showed that in TMEM67 knockdown zebrafish with a hydrocephalus phenotype, injection with mutant morpholinos containing the G132A or c.2758delT mutations did not rescue the phenotype.
For discussion of the 1-bp deletion (c.2758delT, NM_153704.5) in the TMEM67 gene that was found in compound heterozygous state in a patient with COACH syndrome-1 (COACH1; 216360) by Lee et al. (2017), see 609884.0027.
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