Biomedical subjects

M Muenke

Publications and source records attributed to M Muenke.

At least 55 records · Page 3Linked to original sources

PubMed1998

Analysis of patients with craniosynostosis syndromes for a pro246Arg mutation of FGFR4.

An identical amino acid substitution in fibroblast growth factor receptors (FGFR) 1, 2 and 3 occurs in patients with different craniosynostosis syndromes. We tested 113 patients with various craniosynostosis syndromes for the analogous Pro246Arg mutation in FGFR4 by a PCR-restriction enzyme assay. None of the patients displayed this change nor other mutations in the conserved linker region, as test by SSCP analysis. Mutations in this domain of FGFR4 are unlikely to contribute significantly to craniosynostosis in humans.

Acrocephalosyndactylia↗

PubMed1998

Analysis of the human Sonic Hedgehog coding and promoter regions in sacral agenesis, triphalangeal thumb, and mirror polydactyly.

The human Sonic Hedgehog gene (SHH) is one of the vertebrate homologs related to the Drosophila segment polarity gene hedgehog. The entire coding and promoter region of the SHH gene, including 2 kb 5' of the transcriptional start site has been screened for mutations in families with autosomal dominant sacral agenesis and autosomal dominant triphalangeal thumb, two conditions previously known to be linked to 7q36. We have also studied the SHH gene in five families with mirror polydactyly associated with tibial hemimelia and in 51 unrelated patients with neural tube defects. Except for two sequence variants in exon 3, no mutations were found in these disease categories. OFF

Abnormalities, Multiple↗

PubMed1998

Identification of a genetic cause for isolated unilateral coronal synostosis: a unique mutation in the fibroblast growth factor receptor 3.

To determine whether the autosomal dominant fibroblast growth factor receptor 3 (FGFR3) Pro250Arg mutation causes anterior plagiocephaly, patients with either apparently sporadic unicoronal synostosis (N = 37) or other forms of anterior plagiocephaly (N = 10) were studied for this mutation. Of 37 patients with unicoronal synostosis, 4 tested positive for the Pro250Arg mutation in FGFR3, and 33 were negative for this mutation. In three mutation positive patients with full parental studies, a parent with an extremely mild phenotype was found to carry the same mutation. None of the 6 patients with nonsynostotic plagiocephaly and none of the 4 patients with additional suture synostosis had the FGFR3 mutation. Because it is impossible to predict the FGFR3 Pro250Arg mutation status based on clinical examination alone, all patients with unicoronal synostosis should be tested for it. To assess their recurrence risk, all parents of mutation positive patients should be tested regardless of their clinical findings, because the phenotype can be extremely variable and without craniosynostosis.

Craniosynostoses↗

PubMed1998

Human developmental disorders and the Sonic hedgehog pathway.

Sonic hedgehog (Shh) is a morphogen that is crucial for normal development of a variety of organ systems, including the brain and spinal cord, the eye, craniofacial structures, and the limbs. Mutations in the human SHH gene and genes that encode its downstream intracellular signaling pathway cause several clinical disorders. These include holoprosencephaly (HPE, the most common anomaly of the developing forebrain), nevoid basal cell carcinoma syndrome, sporadic tumors, including basal cell carcinomas, and three distinct congenital disorders: Greig syndrome Pallister-Hall syndrome, and isolated postaxial polydactyly. These conditions caused by abnormalities in the SHH pathway demonstrate the crucial role of SHH in complex developmental processes, and molecular analyses of these disorders provide insight into the normal function of the SHH pathway in human development.

Animals↗

PubMed1998

Holoprosencephaly: a paradigm for the complex genetics of brain development.

Holoprosencephaly (HPE) is the most common major developmental defect of the forebrain in humans. Clinical expression is variable, ranging from a small brain with a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial HPE. Significant aetiological heterogeneity exists in HPE and includes both genetic and environmental causes. Recently, defects in the cell signalling pathway involving the Sonic Hedgehog (SHH) gene, as well as defects in the cholesterol biosynthesis, have been shown to cause HPE in humans. These discoveries and current genetic approaches serve as a paradigm for studying normal and abnormal brain morphogenesis.

Animals↗

PubMed1998

Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired.

Holoprosencephaly (HPE) is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. On the basis of molecular analysis of a series of patients with hemizygous deletions of the long arm of chromosome 13, we have defined a discrete region in band 13q32 where deletion leads to major developmental anomalies (the 13q32 deletion syndrome). This approximately 1-Mb region lies between markers D135136 and D13S147. Patients in which this region is deleted usually have major congenital malformations, including brain anomalies such as HPE or exencephaly, and digital anomalies such as absent thumbs. We now report that human ZIC2 maps to this critical deletion region and that heterozygous mutations in ZIC2 are associated with HPE. Haploinsufficiency for ZIC2 is likely to cause the brain malformations seen in 13q deletion patients.

Amino Acid Sequence↗

PubMed1998

Opitz G/BBB syndrome in Xp22: mutations in the MID1 gene cluster in the carboxy-terminal domain.

The MID1 gene in Xp22 codes for a novel member of proteins containing a RING finger, B-box, coiled-coil and a conserved C-terminal domain. Initially, three mutations in the C-terminal region were found in patients with Opitz G/BBB syndrome, a defect of midline development. Here we have determined the complete gene structure of the MID1 gene and have analyzed all nine exons for mutations in a set of 40 unrelated Opitz G/BBB patients. We now report six additional mutations all clustered in the carboxy-terminal domain of the MID1 protein. These data suggest that this conserved domain of the B-box proteins may play a fundamental role in the pathogenesis of Opitz syndrome and in morphogenetic events at the midline during blastogenesis.

Abnormalities, Multiple↗

PubMed1998

Holoprosencephaly: from Homer to Hedgehog.

Holoprosencephaly (HPE), a common developmental defect affecting the forebrain and face, is etiologically heterogeneous and exhibits wide phenotypic variation. Graded degrees of severity of the brain malformation are also reflected in the highly variable craniofacial malformations associated with HPE. In addition, individuals with microforms of HPE, who usually have normal cognition and normal brain imaging, are at risk for having children with HPE. Some obligate carriers for HPE may not have any phenotypic abnormalities. Recurrent chromosomal rearrangements in individuals with HPE suggest loci containing genes important for brain development, and abnormalities in these genes may result in HPE. Recently, Sonic Hedgehog (SHH) was the first gene identified as causing HPE in humans. Proper function of SHH depends on cholesterol modification. Other candidate genes that may be involved in HPE include components of the SHH pathway, elements involved in cholesterol metabolism, and genes expressed in the developing forebrain.

Abnormalities, Multiple↗

PubMed1998

Imaging studies in a unique familial dysmyelinating disorder.

We report the imaging findings in five patients with a unique dysmyelinating disorder. MR studies of these infants showed obstructive hydrocephalus caused by mass effect produced by an enlarged cerebellum. The white matter of an enlarged cerebrum and cerebellum showed delayed myelination. Proton spectroscopy showed normal N-acetylaspartate (NAA) levels. While the dysmyelinating disorder was clearly differentiated from Canavan disease by an absence of elevated NAA and differing histopathologic findings and autosomal-dominant inheritance pattern, there were similarities to this disease in the presentation and, to some extent, in the initial imaging findings.

Adolescent↗

PubMed1997

Genomic structure, sequence, and mapping of human FGF8 with no evidence for its role in craniosynostosis/limb defect syndromes.

Fibroblast growth factor-8 (Fgf8) is a recently identified growth factor that stimulates the androgen-dependent growth of mouse mammary carcinoma cells. Evidence from mouse development also shows that Fgf8 may play an important role in growth and patterning of limbs, face, and the central nervous system. We describe here the human FGF8 genomic sequence and demonstrate conservation between the human and mouse sequences, including alternatively spliced exons in the mouse. Mapping of FGF8 by FISH using an FGF8-containing bacterial artificial chromosome and by genetic linkage using a SSCP variant identified in this study is also reported and refines the FGF8 map location to 10q24. Since FGF8 maps to the same chromosomal region as FGFR2, has indeed been shown to be a ligand for FGFR2, and has an expression pattern consistent with limb and craniofacial anomalies, we have screened two kindreds with Pfeiffer syndrome that were previously linked to markers from 10q24-25 and a large number of individuals with craniosynostosis and limb anomalies for mutations in the coding sequence of FGF8. While no such mutations were identified, a rare polymorphic variant, consisting of an 18-base-pair (six-amino-acid) duplication in exon 1c, is reported that apparently has no clinical effect. Our exclusionary data suggest that mutations in FGF8 would be, at best, an infrequent cause of such disorders.

Amino Acid Sequence↗

PubMed1997

Clinical and molecular analysis in Joubert syndrome.

Joubert syndrome is an autosomal recessive disorder comprising cerebellar hypoplasia, hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The biochemical basis of the Joubert syndrome is unknown. We ascertained a cohort of 50 patients with the Joubert syndrome to evaluate the presence of associated malformations, and to initiate studies leading to the identification of the Joubert syndrome gene. Only 8% of patients had polydactyly, 4% colobomas, 2% renal cysts, and 2% had soft tissue tumors of the tongue. In addition, we evaluated the WNT1 gene as a candidate gene for the Joubert syndrome based on its expression in the developing cerebellum and an associated mutation in the swaying mouse. We searched for mutations in WNT1 in a series of Joubert syndrome patients and no mutations were detected. Our analysis suggests that mutations in WNT1 do not cause the Joubert syndrome.

Abnormalities, Multiple↗

PubMed1997

Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis.

BACKGROUND: The C749G (Pro250Arg) mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) has been found in patients with various types of craniosynostosis. We aimed to find out the proportion of cases of apparently non-syndromic coronal craniosynostosis attributable to this mutation. METHODS: We studied 26 patients with coronal craniosynostosis but no syndromic diagnosis, who were referred to a supra-regional specialist centre. Genomic DNA was analysed by PCR and restriction-enzyme digestion to identify the C749G mutation in FGFR3. Family members of patients found to have the mutation were also tested. FINDINGS: Eight (31%) of the 26 probands were heterozygous for the C749G mutation. In two cases, the mutation showed autosomal dominant transmission with evidence of variable expressivity; the remaining six cases were sporadic. We demonstrated in six families that the mutation had arisen de novo from clinically unaffected parents. INTERPRETATION: The C749G mutation in FGFR3 is a frequent cause of apparently non-syndromic coronal craniosynostosis. Our finding will aid genetic counselling and prenatal diagnosis. The mutation rate at this nucleotide is one of the highest described in the human genome.

Child, Preschool↗

PubMed1997

Cytogenetic rearrangements involving the loss of the Sonic Hedgehog gene at 7q36 cause holoprosencephaly.

Holoprosencephaly (HPE) is a genetically heterogeneous disorder that affects the midline development of the forebrain and midface in humans. As a step toward identifying one of the HPE genes, we have set out to refine the HPE3 critical region on human chromosome 7q36 by analyzing 34 cell lines from families with cytogenetic abnormalities involving 7q, 24 of which are associated with HPE. Genomic clones surrounding the DNA marker D7S104, which has previously been shown to be in the HPE3 critical region, have been examined by fluorescent in situ hybridization and microsatellite analysis of our panel of patient cell lines. We report the analysis of a cluster of four translocation breakpoints within a 300-kb region of 7q36 that serves to define the minimal critical region for HPE3 and that has directed the search for candidate genes. The human Sonic Hedgehog (hSHH) gene maps to this region and has been shown to be HPE3 on the basis of mutations within the coding region of the gene. We present evidence that cytogenetic deletions and/or rearrangements of this region of chromosome 7q containing Sonic Hedgehog, and translocations that may suppress Sonic Hedgehog gene expression through a position effect are common mechanisms leading to HPE.

Body Patterning↗

PubMed1997

Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22.

Opitz syndrome (OS) is an inherited disorder characterized by midline defects including hypertelorism, hypospadias, lip-palate-laryngotracheal clefts and imperforate anus. We have identified a new gene on Xp22, MID1 (Midline 1), which is disrupted in an OS patient carrying an X-chromosome inversion and is also mutated in several OS families. MID1 encodes a member of the B-box family of proteins, which contain protein-protein interaction domains, including a RING finger, and are implicated in fundamental processes such as body axis patterning and control of cell proliferation. The association of MID1 with OS suggests an important role for this gene in midline development.

Abnormalities, Multiple↗

PubMed1997

Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.

Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been described in five craniosynostosis syndromes. In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family. A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome. Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the Ser252Phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlights the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. The description of independent, complex nucleotide substitutions involving identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm.

Adult↗

PubMed1997

Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly.

Holoprosencephaly (HPE) is the most common brain anomaly in humans, involving abnormal formation and septation of the developing central nervous system. Among the heterogeneous causes of HPE, mutations in the Sonic Hedgehog (SHH) gene have been shown to result in an autosomal dominant form of the disorder. Here we describe a total of five different mutations in the processing domain encoded by exon 3 of SHH in familial and sporadic HPE. This is the first instance in humans where SHH mutations in the domain responsible for autocatalytic cleavage and cholesterol modification of the N-terminal signaling domain of the protein have been observed.

Alanine↗

PubMed1997

A novel phenotypic pattern in X-linked inheritance: craniofrontonasal syndrome maps to Xp22.

Craniofrontonasal syndrome (CFNS, OMIM 304110) is a distinctive genetic disorder whose main clinical manifestations include coronal synostosis, widely spaced eyes, clefting of the nasal tip and various skeletal anomalies. CFNS originally was thought to be transmitted as an autosomal dominant trait, but recent studies suggest that it is X-linked dominant, whereby all daughters of males are affected, whereas none of their sons are affected. Here we report data confirming that CFNS is X-linked, mapping to a 13 cM interval in Xp22 with a maximum two-point lod score of 3.9 (theta = 0) at DXS8022 and a multipoint lod score of 5.08 at DXS1224. Detailed phenotypic analysis shows that females are more severely affected than males, a highly unusual characteristic for an X-linked disorder. CFNS represents the first multiple congenital anomaly syndrome with this unusual phenotypic pattern of X-linked inheritance.

Chromosome Mapping↗

PubMed1997

A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome.

The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis.

Adult↗