Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Joubert syndrome is an autosomal-recessive disorder characterized by cerebellar hypoplasia, hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The biochemical and genetic basis of Joubert syndrome is unknown and a specific chromosomal locus for this disorder has not been identified. Review of this disorder and related syndromes suggests that (1) hypoplasia of the cerebellar vermis in Joubert syndrome is frequently associated with a complex brain stem malformation represented as the "molar tooth sign" on magnetic resonance imaging, (2) the "molar tooth sign" could be present in association with the Dandy-Walker malformation and occipital encephalocele, (3) cerebellar hypoplasia is present in conditions related to Joubert syndrome such as Arima syndrome; Senior-Loken syndrome; cerebellar vermian hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis syndrome; and juvenile nephronophthisis due to NPH1 mutations, and (4) the brainstem-vermis malformation spectrum is probably caused by at least two and probably several genetic loci. We have ascertained previously a cohort of 50 patients with a putative diagnosis of Joubert syndrome in order to evaluate the presence of associated malformations, and to initiate studies leading to the identification of genes causing Joubert and related syndromes. Among the associated malformations found in patients ascertained as having Joubert syndrome, 8% of patients had polydactyly, 4% had ocular colobomas, 2% had renal cysts, and 2% had soft-tissue tumors of the tongue. The WNT1 gene has been tested as a candidate gene for Joubert syndrome based on its expression in the developing cerebellum and an associated mutation in the swaying mouse. A search for mutations in WNT1 in a series of patients with Joubert syndrome did not detect mutations at this locus. This analysis suggested that mutations in WNT1 might not have a significant role in Joubert syndrome, and other functional candidate genes related to development of the cerebellum need to be examined. A genome-wide linkage analysis carried out in 10 Joubert syndrome pedigrees did not identify a specific chromosomal locus for this disorder. This observation, along with those from clinical studies, provides further evidence that Joubert and related syndromes are genetically heterogeneous.
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PMID:Clinical nosologic and genetic aspects of Joubert and related syndromes. 1051 39

Joubert syndrome (JS) is an autosomal recessive multisystem disease characterized by cerebellar vermis hypoplasia with prominent superior cerebellar peduncles (the "molar tooth sign" [MTS] on axial magnetic resonance imaging), mental retardation, hypotonia, irregular breathing pattern, and eye-movement abnormalities. Some individuals with JS have retinal dystrophy and/or progressive renal failure characterized by nephronophthisis (NPHP). Thus far, no mutations in the known NPHP genes, particularly the homozygous deletion of NPHP1 at 2q13, have been identified in subjects with JS. A cohort of 25 subjects with JS and either renal and/or retinal complications and 2 subjects with only juvenile NPHP were screened for mutations in the NPHP1 gene by standard methods. Two siblings affected with a mild form of JS were found to have a homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with NPHP alone. A control subject with NPHP and with a homozygous NPHP1 deletion was also identified, retrospectively, as having a mild MTS and borderline intelligence. The NPHP1 deletion represents the first molecular defect associated with JS in a subset of mildly affected subjects. Cerebellar malformations consistent with the MTS may be relatively common in patients with juvenile NPHP without classic symptoms of JS.
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PMID:The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. 1513 99

Joubert syndrome (JS) is an autosomal recessive disorder marked by agenesis of the cerebellar vermis, ataxia, hypotonia, oculomotor apraxia, neonatal breathing abnormalities, and mental retardation. Despite the fact that this condition was described >30 years ago, the molecular basis has remained poorly understood. Here, we identify two frameshift mutations and one missense mutation in the AHI1 gene in three consanguineous families with JS, some with cortical polymicrogyria. AHI1, encoding the Jouberin protein, is an alternatively spliced signaling molecule that contains seven Trp-Asp (WD) repeats, an SH3 domain, and numerous SH3-binding sites. The gene is expressed strongly in embryonic hindbrain and forebrain, and our data suggest that AHI1 is required for both cerebellar and cortical development in humans. The recently described mutations in NPHP1, encoding a protein containing an SH3 domain, in a subset of patients with JS plus nephronophthisis, suggest a shared pathway.
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PMID:Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. 1546 82

Joubert syndrome (JBTS) is an autosomal recessive multisystem disease characterized by cerebellar vermis aplasia, mental retardation, muscular hypotonia, an irregular breathing pattern in the neonatal period and abnormal eye movements. Some individuals have progressive renal failure characterized by nephronophthisis (NPHP) and/or retinal dystrophy. Homozygous deletions of NPHP1 on chromosome 2q13 have been identified in individuals with NPHP-associated JBTS. Recently, mutations in AHI1 on chromosome 6q23.3 were found in JBTS patients without NPHP. Here, by direct sequencing, we identify novel truncating mutations within AHI1 in affected patients from two families. One patient had the association of JBTS and NPHP with chronic renal failure. This is the first report of AHI1 mutations causing JBTS associated with NPHP, confirming the clinical and genetic heterogeneity of NPHP.
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PMID:Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome. 1624 Jan 61

Type 1 nephronophthisis (NPHP) with homozygous deletions of nephrocystin [NPHP1, DEL] has been considered a pure renal disorder, but co-occurrence of extrarenal symptoms, mainly retinitis pigmentosa, is observed in a subset of patients. Recently, [NPHP1, DEL] has been detected in three patients with Joubert syndrome-related disorders (JSRDs), who associated neurological signs with a peculiar neuroradiological malformation known as the 'molar tooth sign' (MTS). To define the frequency of JSRD spectrum in NPHP1 patients, we re-examined 56 cases with [NPHP1, DEL] and found an overall incidence of 8.9% (five out 56 patients). All had small hyperechoic kidneys and had developed advanced renal failure within 15 years. Two patients presented the complete features of JSRD with cerebello-renal-retinal association and MTS. Two others showed, instead, severe intentional tremor and thick superior cerebellar peduncles on brain magnetic resonance imaging (MRI), and one of them had associated retinopathy. The fifth patient presented with hypotonia, developmental delay, central deafness, and ataxia associated with Leber congenital amaurosis and liver fibrosis but with normal brain MRI. Marked intrafamilial variability of associated extrarenal symptoms was observed in familial cases. Deletion extension did not differ in patients with isolated renal phenotype and in those with associated neurological symptoms. In conclusion, neurological defects varying from subtle involvement of cerebellum with thickened peduncle to both JSRD and diffuse central hypotonia are frequent in [NPHP1, DEL] patients. Prevalence of such association may justify systematic neurological and neuroradiological evaluation.
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PMID:Nephronophthisis type 1 deletion syndrome with neurological symptoms: prevalence and significance of the association. 1690 87

Joubert syndrome (JS) 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 JS type B. JS is a genetically heterogeneous condition with mutations in two genes, AHI1 and CEP290, identified to date. In addition, NPHP1 deletions identical to those that cause juvenile nephronophthisis have been identified in a subset of patients with a mild form of cerebellar and brainstem anomaly. Occipital encephalocele and/or polydactyly have occasionally been reported in some patients with JS, and these phenotypic features can also be observed in Meckel-Gruber syndrome (MKS). MKS is a rare, autosomal recessive lethal condition characterized by central nervous system malformations (typically, occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. Since there is obvious phenotypic overlap between JS and MKS, we hypothesized that mutations in the recently identified MKS genes, MKS1 on chromosome 17q and MKS3 on 8q, may be a cause of JS. After mutation analysis of MKS1 and MKS3 in a series of patients with JS (n=22), we identified MKS3 mutations in four patients with JS, thus defining MKS3 as the sixth JS locus (JBTS6). No MKS1 mutations were identified in this series, suggesting that the allelism is restricted to MKS3.
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PMID:The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. 1716 Sep 6

Joubert syndrome (JS) and related disorders are characterized by the 'molar tooth sign' (cerebellar vermis hypoplasia and brainstem anomalies) on MRI, hypotonia, developmental delay, ataxia, irregular breathing pattern and abnormal eye movements. Combinations of additional features such as polydactyly, ocular coloboma, retinal dystrophy, renal disease, hepatic fibrosis, encephalocele, and other brain malformations define clinical sub-types. Recent identification of the NPHP1, AHI1, and CEP290 genes has started to reveal the molecular basis of JS, which may implicate the primary cilium in these disorders. Additional genes remain to be identified.
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PMID:Joubert syndrome (and related disorders) (OMIM 213300). 1737 24

Joubert syndrome (JS) is an autosomal recessive disorder that is described in patients with cerebellar ataxia, mental retardation, hypotonia, and neonatal respiratory dysregulation. Kidney involvement (nephronophthisis or cystic renal dysplasia) is associated with JS in one fourth of known cases. Mutations in three genes--AHI1, NPHP1, and NPHP6--have been identified in patients with JS. However, because NPHP1 mutations usually cause isolated nephronophthisis, the factors that predispose to the development of neurologic involvement are poorly understood. In an attempt to identify such genetic determinants, a cohort of 28 families with nephronophthisis and at least one JS-related neurologic symptom were screened for mutations in AHI1, NPHP1, and NPHP6 genes. NPHP1 and NPHP6 homozygous or compound heterozygous mutations were found in 13 (46%) and six (21%) unrelated patients, respectively. Two of the 13 patients with NPHP1 mutations carried either a heterozygous truncating mutation in NPHP6 or a heterozygous missense mutation in AHI1. Furthermore, five patients with NPHP1 mutations carried the AHI1 variant R830W, which was predicted to be "possibly damaging" and was found with significantly higher frequency than in healthy control subjects and in patients with NPHP1 mutations without neurologic symptoms (five of 26 versus four of 276 and three of 152 alleles; P < 0.001 and P < 0.002, respectively). In contrast to the variable neurologic and milder retinal phenotype of patients with NPHP1 mutations, patients with NPHP6 mutations presented with a more severe neurologic and retinal phenotype. In conclusion, NPHP1 and NPHP6 are major genes of nephronophthisis associated with JS. Epistatic effects that are provided by heterozygous NPHP6 and AHI1 mutations and variants may contribute to the appearance of extrarenal symptoms in patients with NPHP1 mutations.
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PMID:High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. 1740 9

Meckel syndrome (MKS) is a rare lethal autosomal recessive disorder characterized by the presence of occipital encephalocele, cystic kidneys, fibrotic changes of the liver and polydactyly. Joubert syndrome (JS)-related disorders (JSRDs) or cerebello-oculo-renal syndromes (CORS) are a group of recessively inherited conditions characterized by a molar tooth sign (MTS) on cranial MRI, a set of core clinical features (developmental delay/mental retardation, hypotonia, ataxia, episodic breathing abnormalities, abnormal eye movements) and variable involvement of other systems including renal, ocular, central nervous system, craniofacial, hepatic, and skeletal. A significant clinical overlap between MKS and JSRD/CORS has been recognized in the literature. We describe a group of 10 Hutterite patients, of which 7 had been previously diagnosed with MKS, with a JSRD. Clinical features include variable early mortality, cognitive handicap, a characteristic dysmorphic facial appearance, hypotonia, ataxia, abnormal breathing pattern, nystagmus, and MTS on MRI. Additional features include occipital encephalocele, posterior fossa fluid collections resembling Dandy-Walker malformation, hydrocephalus, coloboma, and renal disease. This JSRD is a recognizable dysmorphic syndrome characterized by hypertelorism, deep-set eyes, down-slanting palpebral fissures, ptosis, arched eyebrows with medial sparseness, square nasal tip, short philtrum with tented upper lip, open mouth with down-turned corners, and posteriorly rotated low-set ears. Renal disease is present in 70% of patients and is characterized by cystic kidneys, abnormalities in renal function and hypertension. Homozygous deletions of NPHP1 and the known loci for JS/JSRD and MKS were excluded by identity-by-descent mapping studies suggesting that this condition in the Hutterites represents yet another locus for a JSRD.
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PMID:Meckel syndrome in the Hutterite population is actually a Joubert-related cerebello-oculo-renal syndrome. 1760 1

Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.
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PMID:CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. 1895 Jul 40


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