COACH Syndrome Research Articles

Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy

BackgroundNephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children. Exploring the correlation between the phenotype and genotype of NPHP-RC is helpful...

Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome

COACH syndrome is an autosomal recessive developmental disorder, a subtype of Joubert syndrome and related disorders, characterized by cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Although mutations in TMEM67 (transmembrane protein 67)/MKS3 (Meckel-Gruber syndrome, type 3) were reported to cause COACH syndrome, this causality has not verified by functional studies. In a 20-year-old Korean man, we found cerebellar ataxia, isolated elevation in serum γ-glutamyl transpeptidase (γ-GTP) activity, oligophrenia, the molar tooth sign (MTS) in the brain MR images and congenital hepatic fibrosis (CHF). Two novel compound heterozygous mutations were found in TMEM67 in the patient: i) missense mutation (c.395 G > C and p.Gly132Ala) in exon 3, and ii) deletion in exon 26 (c.2758delT and p.Tyr920ThrfsX40). Western blotting showed that the p.Tyr920ThrfsX40 mutation accelerates turnover of the TMEM67 protein. Although wild-type human TMEM67 RNA rescued phenotypes of zebrafish embryos injected with anti-sense oligonucleotide morpholinos against tmem67, the two human TMEM67 RNAs individually harboring the two mutations did not. Finally, Wnt signaling, but not Hedgehog signaling, was suppressed in tmem67 morphants. To the best of our knowledge, this is the first report verifying the causality between COACH syndrome and TMEM67, which will further our understanding of molecular pathogenesis of the syndrome.

Broadening the genetic spectrum of “early-onset dementia plus”: Novel TMEM67 variants causing a Coach syndrome & Niemann Pick Type C phenocopy

Broadening the genetic spectrum of “early-onset dementia plus”: Novel TMEM67 variants causing a Coach syndrome & Niemann Pick Type C phenocopy

Dental management for COACH syndrome

Dental management for COACH syndrome

Unraveling the genetics of Joubert and Meckel-Gruber syndromes.

Joubert (JBTS) and Meckel-Gruber (MKS) syndromes are recessive neurodevelopmental conditions caused by mutations in proteins that are structural or functional components of the primary cilium. In this review we provide an overview of their clinical diagnosis, management and molecular genetics. Both have variable phenotypes, extreme genetic heterogeneity, and display allelism both with each other and other ciliopathies. Recent advances in genetic technology have significantly improved diagnosis and clinical management of ciliopathy patients, with the delineation of some general genotype-phenotype correlations. We highlight those that are most relevant for clinical practice, including the correlation between TMEM67 mutations and the JBTS variant phenotype of COACH syndrome. The subcellular localization of the known MKS and JBTS proteins is now well-described, and we discuss some of the contemporary ideas about ciliopathy disease pathogenesis. Most JBTS and MKS proteins localize to a discrete ciliary compartment called the transition zone (TZ), and act as structural components of the so-called "ciliary gate" to regulate the ciliary trafficking of cargo proteins or lipids. Cargo proteins include enzymes and transmembrane proteins that mediate intracellular signaling. The disruption of TZ function may contribute to the ciliopathy phenotype by altering the composition of the ciliary membrane or axoneme, with impacts on essential developmental signaling including the Wnt and Shh pathways as well as the regulation of secondary messengers such as inositol-1,4,5-trisphosphate (InsP3) and cAMP. However, challenges remain in the interpretation of the pathogenic potential of genetic variants of unknown significance, and in the elucidation of the molecular mechanisms of phenotypic variability in JBTS and MKS. The further genetic and functional characterization of these conditions is essential to prioritize patients for new targeted therapies.

Ciliopathies with Hepatic Involvement the Broad Phenotypical Spectrum of TMEM67 Mutations

Case Study: Ciliopathies are a large group of human disorders caused by dysfunction of the primary cilium. The most important ciliopathies comprise cystic kidney diseases, Joubert syndrome, Meckel–Gruber syndrome and the congenital oculomotor apraxia type Cogan II. Because of major genetic and clinical overlap, a clear cut genotype–phenotype correlation was almost impossible in the past. Recently TMEM67, encoding the transmembrane protein Meckelin, has been in the scientific focus as a genetic cause of various ciliopathies. Mutations in TMEM67 have been reported for nephronophthisis, Meckel-Gruber syndrome, Joubert syndrome, and COACH syndrome (coloboma, oligophrenia, ataxia, cerebellar vermis hypoplasia, and liver fibrosis). There is a wide range of clinical findings in patients with TMEM67 mutations. However, liver involvement in terms of a congenital hepatic fibrosis has been found as a unifying feature in almost all the patients. This makes TMEM67 one of the first ciliary genes with a relatively strong genotype–phenotype correlation. We report four patients with mutations in TMEM67 presenting very different clinical phenotypes, one of them showing oculomotor apraxia. To our knowledge, this is the first time that a compound heterozygous TMEM67 mutation is described in a patient with oculomotor apraxia type Cogan II. All four patients present congenital liver fibrosis and elevated liver enzymes, matching the genotype–phenotype correlation described earlier.

Molar Tooth Sign with Deranged Liver Function Tests: An Indian Case with COACH Syndrome.

We report the first genetically proven case of COACH syndrome from the Indian subcontinent in a 6-year-old girl who presented with typical features of Joubert syndrome along with hepatic involvement. Mutation analysis revealed compound heterozygous missense mutation in the known gene TMEM67 (also called MKS3).

The ciliary protein Meckelin/TMEM67 interacts with HDAC6: possible implications for primary cilia stability

Ciliopathies are a group of autosomal recessive disorders, characterized by defect in central nervous system, that include several, partially overlapping, syndromes such Meckel-Gruber syndrome and COACH syndrome. Ciliopathies are caused by mutations in genes encoding protein of the primary cilium, as Jouberin and Meckelin (TMEM67). Meckelin is a receptor localized to the ciliary membrane and at the cell surface of polarized cells; it interacts with citoskeletal protein participating in ciliogenesis via remodelling of cytoskeleton. Histone Deacetylase (HDAC) 6 is a cytoplasmic deacetylase, that localize to microtubules in a variety of cultured cells, and participate in the deacetylation of the major component of the cilia axoneme, alpha-tubulin, a process that leads to reduced microtubule stability. Moreover, HDAC6 has also been implicated both in cilia resorption and disassembly, through its interaction with Aurora A kinase, that localize to basal bodies. In the present work we show that MKS3 interacts with HDAC6 in MKS3 overexpressing HEK293 cells and in ciliated IMCD3 cells. Moreover, we confirmed this interaction in mouse embryonic stem cells, used as an in vitro model of neurogenesis. In this cellular context, deacetylase activity assays performed on MKS3 immunoprecipitated complexes showed high HDAC activity, which was lost in the presence of a specific HDAC6 inhibitor. Altogether these results reveal an unpredictable interaction between Meckelin and HDAC6, shedding light on a putative, novel role of Meckelin in controlling ciliary microtubules acetylation/deacetylation and primary cilia stability.

Identification of hemostatic genes expressed in human and rat leg muscles and a novel gene (LPP1/PAP2A) suppressed during prolonged physical inactivity (sitting)

BackgroundPartly because of functional genomics, there has been a major paradigm shift from solely thinking of skeletal muscle as contractile machinery to an understanding that it can have roles in paracrine and endocrine functions. Physical inactivity is an established risk factor for some blood clotting disorders. The effects of inactivity during sitting are most alarming when a person develops the enigmatic condition in the legs called deep venous thrombosis (DVT) or “coach syndrome,” caused in part by muscular inactivity. The goal of this study was to determine if skeletal muscle expresses genes with roles in hemostasis and if their expression level was responsive to muscular inactivity such as occurs in prolonged sitting.MethodsMicroarray analyses were performed on skeletal muscle samples from rats and humans to identify genes associated with hemostatic function that were significantly expressed above background based on multiple probe sets with perfect and mismatch sequences. Furthermore, we determined if any of these genes were responsive to models of physical inactivity. Multiple criteria were used to determine differential expression including significant expression above background, fold change, and non-parametric statistical tests.ResultsThese studies demonstrate skeletal muscle tissue expresses at least 17 genes involved in hemostasis. These include the fibrinolytic factors tetranectin, annexin A2, and tPA; the anti-coagulant factors TFPI, protein C receptor, PAF acetylhydrolase; coagulation factors, and genes necessary for the posttranslational modification of these coagulation factors such as vitamin K epoxide reductase. Of special interest, lipid phosphate phosphatase-1 (LPP1/PAP2A), a key gene for degrading prothrombotic and proinflammatory lysophospholipids, was suppressed locally in muscle tissue within hours after sitting in humans; this was also observed after acute and chronic physical inactivity conditions in rats, and exercise was relatively ineffective at counteracting this effect in both species.ConclusionsThese findings suggest that skeletal muscle may play an important role in hemostasis and that muscular inactivity may contribute to hemostatic disorders not only because of the slowing of blood flow per se, but also potentially because of the contribution from genes expressed locally in muscles, such as LPP1.

Progression of hepatic fibrosis observed by repeated liver biopsies in an adult case of COACH syndrome

Progression of hepatic fibrosis observed by repeated liver biopsies in an adult case of COACH syndrome

Clinical and molecular features of Joubert syndrome and related disorders

Joubert syndrome (JBTS; OMIM 213300) is a rare, autosomal recessive disorder characterized by a specific congenital malformation of the hindbrain and a broad spectrum of other phenotypic findings that is now known to be caused by defects in the structure and/or function of the primary cilium. The complex hindbrain malformation that is characteristic of JBTS can be identified on axial magnetic resonance imaging and is known as the molar tooth sign (MTS); other diagnostic criteria include intellectual disability, hypotonia, and often, abnormal respiratory pattern and/or abnormal eye movements. In addition, a broad spectrum of other anomalies characterize Joubert syndrome and related disorders (JSRD), and may include retinal dystrophy, ocular coloboma, oral frenulae and tongue tumors, polydactyly, cystic renal disease (including cystic dysplasia or juvenile nephronophthisis), and congenital hepatic fibrosis. The clinical course can be variable, but most children with this condition survive infancy to reach adulthood. At least eight genes cause JSRD, with some genotype-phenotype correlations emerging, including the association between mutations in the MKS3 gene and hepatic fibrosis characteristic of the JSRD subtype known as COACH syndrome. Several of the causative genes for JSRD are implicated in other ciliary disorders, such as juvenile nephronophthisis and Meckel syndrome, illustrating the close association between these conditions and their overlapping clinical features that reflect a shared etiology involving the primary cilium.

Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)

ObjectiveTo identify genetic causes of COACH syndromeBackgroundCOACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis...

The first Japanese case of COACH syndrome

COACH syndrome is a disorder characterized by hypoplasia of cerebellar vermis, oligophrenia, congenital ataxia, coloboma and hepatic fibrosis, and 21 cases have been reported to date. Here we describe the first Japanese case of COACH syndrome, who was diagnosed at the age of 37 years and never progressed to liver failure. The patient was found to have delayed developmental milestones at the age of 5 months and mental retardation at the age of 7 years. She had been treated for hepatopathy of unknown origin from the age of 22 years. She was admitted to Hiroshima University Hospital at the age of 37 years after the identification of esophageal varices on a routine upper endoscopy. Computed tomography of the abdomen revealed portal hypertension and splenomegaly, and liver biopsy showed liver fibrosis. In addition, she had coordination disorder and dysarthria. Brain magnetic resonance images revealed hypoplasia of cerebellar vermis. The final diagnosis was COACH syndrome. She underwent endoscopic injection sclerotherapy for esophageal varices. From that point until her death from ovarian cancer at the age of 41 years, the liver function tests were stable without an episode of hematemesis. Physicians should be aware of COACH syndrome when they examine young patients who present with hepatopathy, portal hypertension of unknown origin and cerebellar ataxia.

MKS3/TMEM67mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.

Identification of hemostatic genes expressed in human and rat leg muscles and a novel gene suppressed by sitting (LPP1/PAP2A)

A major paradigm shift largely because of functional genomics has been that tissues like muscle, heart, and adipose tissue are multifunctional, and can have paracrine or endocrine functions. Physical inactivity is an established risk factor for some blood clotting disorders. The effects of inactivity are most alarming when a person develops the enigmatic condition in the legs called deep venous thrombosis (DVT) or "coach syndrome," caused in part by muscular inactivity. PURPOSE: This study addressed the need to identify with microarrays, hemostasis genes expressed in leg skeletal muscle tissue, and with a translational approach, a novel candidate gene(s) that is most sensitive to physical inactivity. METHODS: Global gene expression was assessed in deep leg muscle of humans using Affymetrix microarrays after 12 hours of sitting and after normal low-intensity standing and intermittent ambulatory activity. Global gene expression of the rat soleus muscle was also assessed with microarrays after 12 hours of physical inactivity (e.g., not standing), after 12 hours of physical inactivity followed by 2 hours of walking on a treadmill, after 11 days of intermittent physical inactivity (10 hr/day) and compared to the referent control of normally caged rats with voluntary standing and intermittent cage movements. RESULTS: These studies demonstrate that human skeletal muscle tissue expresses at least 22 genes involved in hemostasis. These include the fibrinolytic factors tetranectin, annexin A2, and tPA; the anti-coagulant factors TFPI, protein C receptor, PAF acetylhydrolase; coagulation factors, and genes necessary for the posttranslational modification of these coagulation factors such as vitamin K epoxide reductase. Of special interest, lipid phosphate phosphatase-1 (LPP1/PAP2a), a key gene for degrading prothrombotic and proinflammatory lysophospholipids, was suppressed locally within muscle tissue within hours after sitting; this was also observed after acute and chronic physical inactivity conditions in rats, and exercise was relatively ineffective at counteracting this effect. CONCLUSIONS: These findings suggest that muscular inactivity contributes to hemostatic disorders not only because of the slowing of blood flow per se, but also potentially because of the contribution from genes expressed locally in muscles, such as LPP1.

Model for end-stage liver disease (MELD) exception for unusual metabolic liver diseases

Metabolic liver disease is the underlying diagnosis in only a small proportion of patients who undergo liver transplantation (LT), but for these patients, LT is lifesaving. Patients with metabolic liver disease often do not present with typical findings of end-stage liver disease and require special consideration and scrutiny concerning the appropriateness and timing of LT. Liverbased metabolic disease is classified into 3 types: (1) disease that causes structural liver damage with liver failure or cirrhosis, (2) metabolic disease without structural liver damage that affects other organs (especially the central nervous system), and (3) metabolic disease with systemic deficiencies that are partially represented in the liver. There may be overlap in presentation, with some disease forms presenting either with or without structural liver disease. General considerations that affect review board decisions may include the relative contraindication of the use of living-related donor organs and the unpredictable metabolic course that may cause severe central nervous system complications in several of these disease states. Also, although many of these diseases present mostly in children, adolescents and adults previously managed medically are increasingly presenting for LT consideration when medical management becomes more difficult or complex as they mature.

Successful combined liver and kidney transplant for COACH syndrome and 5‐yr follow‐up

The COACH syndrome is a very rare disorder with cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Nineteen cases with COACH diagnosis have been reported. Neurologic abnormalities are the first symptoms in most cases. Complications of the hepatopathy [portal hypertension, esophageal varices, and gastrointestinal (GI) bleeding] contribute extensively to the morbidity and lethality in the course of the disease. We describe a 28-yr-old female with COACH syndrome resulting in chronic renal and hepatic insufficiency. The patient was found to have significant mental retardation, truncal ataxia, motor abnormality and occulomotor abnormality. She began to develop GI bleeding and encephalopathy because of biopsy-confirmed cirrhosis. We performed combined liver and kidney transplant after challenging discussion. Her postoperative course was uneventful, and she was discharged on the ninth postoperative day (POD). She has not had any problems at 1, 3 and 5-yr follow-up with excellent liver and renal function. This is the first description of successful combined liver and kidney transplant with long-term follow-up. The decision for transplant is challenging because COACH syndrome is rare with only descriptive characterization and patients have non-progressive ataxia and mental retardation. However, our case shows that liver and kidney transplant can be medically successful, and the individuals achieve long-term success if they have a stable neurological condition and an excellent support system.

Diffusion tensor imaging of the brainstem whitematter tract anomaly in a case of COACH syndrome

In this issue of EJREX Sener et al. [1] report a case of cerebral air embolism as a catastrophic complication of a mediastinal tumor. We report here our recent experience with such a dramatic event and show brain CT changes observed in the course of one hour.COACH syndrome is an autosomal recessive disease associates with cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. CNS imaging findings are small cerebellar vermis and abnormal course of superior cerebellar peduncles (SCP), which are similar to Joubert syndrome. We report a case of COACH syndrome, in which diffusion tensor imaging (DTI) of MRI visualized the abnormality of whitematter tract anomaly in brainstem.

COACH syndrome associated with multifocal liver tumors

Here, we describe a 20-yr-old woman with COACH syndome (hypoplasia of Cerebellar vermis, Oligophrenia, congenital Ataxia, Coloboma, and Hepatic fibrosis) developing multiple liver lesions. Epigastric and right upper abdominal pain and lack of appetite led to clinical evaluation. Liver function tests showed an increase in transaminases and cholestatic parameters; α-fetoprotein was in the normal range. Ultrasound and magnetic resonance imaging examinations revealed multiple liver lesions. Histological examinations of ultrasonographically guided biopsies were consistent with regenerative hepatic nodules without features of malignant or dysplastic cells. The sizes of these tumors did not change over a period of 12 months. Our report presents the 10th case of COACH syndrome with a hitherto undescribed association with hepatic tumors.

Cerebellar vermis defect, oligophrenia, congenital ataxia, and hepatic fibrocirrhosis without coloboma and renal abnormalities: report of three cases.

We describe 3 children (2 siblings aged 10 and 3 years, and 1 sporadic case aged 13 years) with cerebellar vermis defect associated with oligophrenia, congenital ataxia, and hepatic fibrocirrhosis. Differently from what is reported in COACH syndrome, coloboma and renal involvement were absent. Since in one patient hepatic involvement was subclinical and early therapy seemed to prevent disease progression, the presence of liver disease should be carefully investigated in any patient with ataxia and midline cerebellar defects.