MID1 mutations in patients with X-linked Opitz G/BBB syndrome

Mutations in the MID1 gene are responsible for the X-linked form of Opitz G/BBB syndrome (OS), a disorder that affects the development of midline structures. OS is characterized by hypertelorism, hypospadias, laryngo-tracheo-esophageal (LTE) abnormalities, and additional midline defects. Cardiac, anal, and neurological defects are also present. The expressivity of OS is highly variable, even within the same family. We reviewed all the MID1 mutations reported so far, in both familial and sporadic cases. The mutations are scattered along the entire length of the gene and consist of missense and nonsense mutations, insertions and deletions, either in-frame or causing frameshifts, and deletions of either single exons or the entire MID1 coding region. The variety of described mutations and the lack of a strict genotype-phenotype correlation confirm the previous suggestion of the OS phenotype being caused by a loss-of-function mechanism. However, although a specific mutation cannot entirely account for the observed phenotype, we observed preferential association between some types of mutation and specific clinical manifestations, e.g., brain anatomical defects and truncating mutations. This may suggest that the pathogenetic mechanism underlying the OS phenotype is more complex and may vary among the affected organs.     

A MID1 gene mutation in a patient with Opitz G/BBB syndrome that altered the 3D structure of SPRY domain

Mutations in the MID1 gene result in X-linked Opitz G/BBB syndrome (OS), a disorder that affects development of midline structures and comprises hypertelorism, cleft lip/palate, hypospadias, and laryngo-tracheo-esophageal abnormalities, and, at times, neurological, anal, and cardiac defects. MID1 gene abnormalities include missense, nonsense, and splicing mutations, small insertions, small deletions, and complex rearrangements. Here, we present a patient with Opitz G/BBB syndrome and a unique MID1 gene point mutation c.1703T相似文献   

Clinical and molecular studies of patients with characteristics of Opitz G/BBB syndrome shows a novel MID1 mutation

Opitz G/BBB syndrome is characterized by midline abnormalities such as hypertelorism, cleft palate, and hypospadias. This syndrome is heterogeneous with an X-linked recessive form caused by mutations in the MID1 gene at band Xp22.3. However, mutations in MID1 have only been identified in 47% of familial cases of X-linked Opitz G/BBB syndrome, and 13% of sporadic cases. We performed a phenotype-genotype analysis of a group of nine new patients with clinical characteristics commonly seen in Opitz G/BBB syndrome, and of previously reported patients. We identified a novel mutation in exon 9 of the MID1 gene, c.1941insTGAGTCATCATCC, leading to a premature termination codon at amino acid 514 in a patient with hypertelorism, apparently low-set ears, a short philtrum, bilateral cleft of lip and palate and hypospadias. This mutation affects the PRY domain of the C-terminus of the MID1 protein.     

A structure-function study of MID1 mutations associated with a mild Opitz phenotype

The X-linked form of Opitz syndrome (OS) affects midline structures and produces a characteristic, but heterogeneous, phenotype that may include severe mental retardation, hypertelorism, broad nasal bridge, widow's peak, cleft lip/cleft palate, congenital heart disease, laryngotracheal defects, and hypospadias. The MID1 gene was implicated in OS by linkage to Xp22. It encodes a 667 amino acid protein that contains a RING finger motif, two B-box zinc fingers, a coiled-coil, a fibronectin type III (FNIII) domain, and a B30.2 domain. Several mutations in MID1 are associated with severe OS. Here, we describe an intelligent male with a milder phenotype characterized by hypertelorism, broad nasal bridge, widow's peak, mild hypospadias, pectus excavatum, and a surgically corrected tracheo-esophageal fistula. He has an above average intelligence and no cleft lip/palate or heart disease. We identified a novel mutation in MID1 (P441L) which is in exon 8 and functionally associated with the FNIII domain. While OS phenotypes have been attributed to mutations in the C-terminal part of MID1, little is currently known about the structure-function relationships of MID1 mutations, and how they affect phenotype. We find from a literature review that missense mutations within the FNIII domain of MID1 are associated with a milder presentation of OS than missense mutations elsewhere in MID1. All truncating mutations (frameshift, insertions/deletions) lead to severe OS. We used homology analysis of the MID1 FNIII domain to investigate structure-function changes caused by our missense mutation. This and other missense mutations probably cause disruption of protein-protein interactions, either within MID1 or between MID1 and other proteins. We correlate these protein structure-function findings to the absence of CNS or palatal changes and conclude that the FNIII domain of the MID1 protein may be involved in midline differentiation after neural tube and palatal structures are completed.     

MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified

Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by defects along the body midline. The disease is characterized by variable expressivity of signs that include hypertelorism, cleft lip and/or palate, laryngo-tracheo-esophageal abnormalities, cardiac defects, and hypospadias. OS patients also present with mental retardation and brain anatomical abnormalities. An autosomal dominant form mapping to chromosome 22 and an X-linked form of OS are known. The gene responsible for the X-linked form of OS, MID1, codes for a member of the Tripartite Motif family of E3 ubiquitin ligases. Here we report 29 novel mutations in 29 unrelated patients of a cohort of 140 male OS cases. These mutations are found in both familial and sporadic cases. They are scattered along the entire length of the gene and are represented by missense and nonsense mutations, insertions and deletions causing frame shift mutations, and deletion of either single exons or the entire gene. The variety of the mutations found confirms that loss-of-function is the mechanism underlying the OS phenotype. Moreover, the low percentage of MID1-mutated OS patients, 47% of the familial and 13% of the sporadic cases, suggests a wider genetic heterogeneity underlying the OS phenotype.     

Diagnosis of a terminal deletion of 4p with duplication of Xp22.31 in a patient with findings of Opitz G/BBB syndrome and Wolf-Hirschhorn syndrome

Opitz G/BBB syndrome (OS) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay and cardiac defects. The X-linked form is caused by mutations in the MID1 gene, while no gene has yet been identified for the autosomal dominant form. Here, we report on a 15-year-old boy who was referred for MID1 mutation analysis with findings typical of OS, including apparent hypertelorism, hypospadias, a history of feeding difficulties, dysphagia secondary to esophageal arteria lusoria, growth retardation and developmental delay. No MID1 mutation was found, but subsequent sub-megabase resolution array CGH unexpectedly documented a 2.34 Mb terminal 4p deletion, suggesting a diagnosis of WHS, and a duplication in Xp22.31. Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome involving terminal chromosome 4p deletions, in particular 4p16.3. WHS is characterized by typical facial appearance ("Greek helmet facies"), mental retardation, congenital hypotonia, and growth retardation. While the severity of developmental delay in this patient supports the diagnosis of WHS rather than OS, this case illustrates the striking similarities of clinical findings in seemingly unrelated syndromes, suggesting common or interacting pathways at the molecular and pathogenetic level. This is the first report of arteria lusoria (esophageal vascular ring) in a patient with WHS.     

Complex rearrangement of the exon 6 genomic region among Opitz G/BBB Syndrome MID1 alterations

Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by developmental defects of midline structures. The most relevant clinical signs are ocular hypertelorism, hypospadias, cleft lip and palate, laryngo-tracheo-esophageal abnormalities, imperforate anus, and cardiac defects. Developmental delay, intellectual disability and brain abnormalities are also present. The X-linked form of this disorder is caused by mutations in the MID1 gene coding for a member of the tripartite motif family of E3 ubiquitin ligases. Here, we describe 12 novel patients that carry MID1 mutations emphasizing that laryngo-tracheo-esophageal defects are very common in OS patients and, together with hypertelorism and hypospadias, are the most frequent findings among the full spectrum of OS clinical manifestations. Besides missense and nonsense mutations, small insertions and deletions scattered along the entire length of the gene, we found that a consistent number of MID1 alterations are represented by the deletion of single coding exons. Deep characterization of one of these deletions reveals, for the first time within the MID1 gene, a complex rearrangement composed of two deletions, an inversion and a small insertion that may suggest the involvement of concurrent non-homologous mechanisms in the generation of the observed structural variant.     

Opitz (BBB/G) syndrome: Oral manifestations

We studied a new case of the G (Opitz BBB/G) syndrome in a 12-year-old boy. Several relatives had partial manifestations of the disorder. A comprehensive dental evaluation of the propositus was conducted; included is, to our knowledge, the first published cephalometric analysis of a G syndrome patient. We reviewed 139 cases of the G syndrome; 48 of them had at least one oral abnormality. These included clefting, micrognathia, ankyloglossia, and high-arched palate. Male G syndrome patients are more likely to have oral anomalies than affected females. © 1992 Wiley-Liss, Inc.     

Opitz (BBB/G) syndrome: oral manifestations.

We studied a new case of the G (Opitz BBB/G) syndrome in a 12-year-old boy. Several relatives had partial manifestations of the disorder. A comprehensive dental evaluation of the propositus was conducted; included is, to our knowledge, the first published cephalometric analysis of a G syndrome patient. We reviewed 139 cases of the G syndrome; 48 of them had at least one oral abnormality. These included clefting, micrognathia, ankyloglossia, and high-arched palate. Male G syndrome patients are more likely to have oral anomalies than affected females.     

Chromosome 22q11.2 deletion in a boy with Opitz (G/BBB) syndrome

This report is on a 14-month-old boy with manifestations of Opitz (G/BBB) syndrome in whom a 22q11.2 deletion was found. Deletion analysis was requested because of some findings in this patient reminiscent of velocardiofacial (VCF) syndrome. The extent of aspiration and of respiratory symptoms in this child is not usually seen in VCF syndrome. Opitz syndrome maps to at least two loci, one on Xp, the other on 22q11.2. © 1996 Wiley-Liss, Inc.     

Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations

Opitz syndrome (OS; MIM 145410 and MIM 300000) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal (LTE) abnormalities, imperforate anus, developmental delay, and cardiac defects. The X-linked form (XLOS) is caused by mutations in the MID1 gene, which encodes a microtubule-associated RBCC protein. In this study, phenotypic manifestations of patients with and without MID1 mutations were compared to determine genotype-phenotype correlations. We detected 10 novel mutations, 5 in familial cases, 2 in sporadic cases, and 3 in families for whom it was not clear if they were familial or sporadic. The genotype and phenotype was compared for these 10 families, clinically diagnosed OS patients found not to have MID1 mutations, and 4 families in whom we have previously reported MID1 mutations. This combined data set includes clinical and mutation data on 70 patients. The XLOS patients with MID1 mutations were less severely affected than patients with MID1 mutations reported in previous studies, particularly in functionally significant neurologic, LTE, anal, and cardiac abnormalities. Minor anomalies were more prevalent in patients with MID1 mutations compared to those without mutations in this study. Female MID1 mutation carriers had milder phenotypes compared to male MID1 mutation carriers, with the most common manifestation being hypertelorism in both sexes. Most of the anomalies found in the patients of the present study do not correlate with the MID1 mutation type, with the possible exception of LTE malformations. This study demonstrates the wide spectrum of severity and manifestations of OS. It also shows that XLOS patients with MID1 mutations may be less severely affected than indicated in prior reports.     

X-linked Opitz G/BBB syndrome: identification of a novel mutation and prenatal diagnosis in a Korean family

X-linked Opitz G/BBB syndrome (XLOS; MIM 300000) is a rare multiple congenital anomaly disorder that is characterized by facial anomalies, laryngeal/tracheal/esophageal defects and genitourinary abnormalities. XLOS is caused by mutations in the MID1 gene which encodes a microtubule-associated RING-Bbox-Coiled-coil (RBCC) protein. We recently found a four-year Korean male patient who was suspected of having XLOS. Mutation analysis of the MID1 gene in the patient and his mother demonstrated that the patient had a novel insertion mutation (c.1798_1799-insC), and his mother was a heterozygous carrier of the mutation. After identification of the causative mutation in this family, prenatal diagnosis of two consecutive fetuses were successfully undertaken. This is the first report on a genetically confirmed case of XLOS in Korea.     

The Opitz syndrome: a new designation for the clinically indistinguishable BBB and G syndromes

The BBB and G syndromes are multiple congenital anomaly (MCA) syndromes characterized by a developmental defect of the midline field. Prominent clinical manifestations are hypertelorism and, in males, hypospadias. Transmission is most likely autosomal dominant in both syndromes. Examination of two new cases and scrutiny of the literature led us to conclude that there are no discriminating qualitative differences between the two conditions. Therefore we propose that they both be designated by the common term "Opitz syndrome."     

X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum

Opitz (or G/BBB) syndrome is a pleiotropic genetic disorder characterized by hypertelorism, hypospadias, and additional midline defects. This syndrome is heterogeneous with an X-linked (XLOS) and an autosomal dominant (ADOS) form. The gene implicated in the XLOS form, MID1, encodes a protein containing a RING-Bbox-Coiled-coil motif belonging to the tripartite motif (TRIM) family. To further clarify the molecular basis of XLOS, we have undertaken mutation analysis of the MID1 gene in patients with Opitz syndrome (OS). We found novel mutations in 11 of 63 male individuals referred to us as sporadic or familial X-linked OS cases. The mutations are scattered throughout the gene, although more are represented in the 3' region. By reviewing all the MID1-mutated OS patients so far described, we confirmed that hypertelorism and hypospadias are the most frequent manifestations, being present in almost every XLOS individual. However, it is clear that laryngo-tracheo-esophageal (LTE) defects are also common anomalies, being manifested by all MID1-mutated male patients. Congenital heart and anal abnormalities are less frequent than reported in literature. In addition, we can include limb defects in the OS clinical synopsis as we found a MID1-mutated patient showing syndactyly. The low frequency of mutations in MID1 and the high variability of the phenotype suggest the involvement of other genes in the OS phenotype.     

CNS midline anomalies in the Opitz G/BBB syndrome: report on 12 Brazilian patients.

We report on 12 Brazilian boys with the Optiz G/BBB syndrome associated with CNS midline anomalies, namely, Dandy-Walker anomaly (two patients), enlarged cisterna magna (four patients), enlarged 4th ventricle (four patients), and callosal a/hypoplasia (two patients). These signs clearly show the involvement of the CNS midline in the Opitz G/BBB syndrome.     

Apparent Opitz BBBG syndrome with a partial duplication of 5p

We describe a patient with a paracentric inversion and partial duplication of chromosome 5p. In addition this patient presented with a malformation pattern consistent with Opitz BBBG syndrome. This implies that the gene responsible for this single gene defect may be located within this duplicated region.