E.C.M. Mariman

Two divergent types of nerve pathology in patients with different P0 mutations in Charcot-Marie-Tooth disease

In seven unrelated patients with a demyelinating motor and sensory neuropathy, we found mutations in exons 2 and 3 of the P sub 0 gene.Morphologic examination of sural nerve biopsy specimens showed a demyelinating process with onion bulb formation in all cases. In four patients, ultrastructural examination demonstrated uncompacted myelin in 23 to 68% of the myelinated fibers, which is in agreement with the widely accepted function of P0 as a homophilic adhesion molecule. Three patients showed normal compact myelin, but morphology was dominated by the abundant occurrence of focally folded myelin. The two divergent pathologic phenotypes exemplify that some mutations act differently on P0 protein formation or function than others, which is probably determined by site and nature of the mutation in the P0 gene. NEUROLOGY 1996;47: 761-765

Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13.1: evidence for genetic heterogeneity

Autosomal, dominantly inherited, non-chromaffin paragangliomas are tumors of the head and neck region occurring with a frequency of 1∶30 000. Genomic imprinting probably influences the expression of the disorder, because tumor development is limited to individuals who have inherited the trait from their father. By linkage analysis and haplotyping of a single large family in which the pattern of inheritance is consistent with genomic imprinting, we have mapped the gene to a 5 cM region of chromosome 11q13.1 between D11S956 and PYGM. A maximum lod score of 7.62 at Θ = 0.0 was obtained for D11S480. This interval does not overlap with a recently assigned locus for glomus tumors in other families: 11q22.3-q23.3. Furthermore, analysis of a second family showing the imprinting phenomenon resulted in the exclusion of the 5 cM area as the location of the disease gene, whereas an indication for linkage was obtained (Z = +2.65) with markers from the distal locus. These observations argue for the presence of two distinct imprinted genes for glomus tumors on 11q. A model for tumor initiation and progression is presented based on all available information.

Analysis of a second family with hereditary non-chromaffin paragangliomas locates the underlying gene at the proximal region of chromosome 11q

The gene for autosomal, dominantly inherited, non-chromaffin paragangliomas has previously been mapped at 11q23-qter by linkage analysis of a single family. In the present study, we have used genetic markers from 11q for the analysis of two distantly related pedigrees with the same disorder. Linkage analysis and haplotyping indicate that the gene underlying the disorder in the present family is located on chromosome 11q proximal to the tyrosinase gene locus (11q14–q21). Closely linked markers are the human homologue of the murine INT2 protooncogene and the anonymous DNA marker D11S527. A maximum lod score of 5.4 (θ=0.0) has been obtained for linkage between the disorder and the chromosomal region defined by these markers. The human INT2 gene can be regarded as a candidate for the disorder on the basis of its expression pattern during embryogenesis in the mouse. However, haplotype analysis indicates that this gene is probably not the predisposing genetic factor in the present family.

Study on the gene and phenotypic characterisation of autosomal recessive demyelinating motor and sensory neuropathy (Charcot-Marie-Tooth disease) with a gene locus on chromosome 5q23-q33

OBJECTIVES To report the occurrence of the autosomal recessive form of demyelinating Charcot-Marie-Tooth disease (CMT) with a locus on chromosome 5q23–33 in six non-related European families, to refine gene mapping, and to define the disease phenotype. METHODS In an Algerian patient with autosomal recessive demyelinating CMT mapped to chromosome 5q23-q33 the same unique nerve pathology was established as previously described in families with a special form of autosomal recessive demyelinating CMT. Subsequently, the DNA of patients with this phenotype was tested from five Dutch families and one Turkish family for the 5q23-q33 locus. RESULTS These patients and the Algerian families showed a similar and highly typical combination of clinical and morphological features, suggesting a common genetic defect. A complete cosegregation for markers D5S413, D5S434, D5S636, and D5S410 was found in the families. Haplotype construction located the gene to a 7 cM region between D5S643 and D5S670. In the present Dutch families linkage disequilibrium could be shown for various risk alleles and haplotypes indicating that most of these families may have inherited the underlying genetic defect form a common distant ancestor. CONCLUSIONS This study refines the gene localisation of autosomal recessive demyelinating CMT, mapping to chromosome 5q23–33 and defines the phenotype characterised by a precocious and rapidly progressive scoliosis in combination with a relatively mild neuropathy and a unique pathology. Morphological alterations in Schwann cells of the myelinated and unmyelinated type suggest the involvement of a protein present in both Schwann cell types or an extracellular matrix protein rather than a myelin protein. The combination of pathological features possibly discerns autosomal recessive demyelinating CMT with a gene locus on chromosome 5q23–33 from other demyelinating forms of CMT disease.

Evidence for genetic heterogeneity underlying hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is a disorder of the peripheral nervous system, the cause of which has recently been identified as a deletion on chromosome 17p. The deletion corresponds to the duplication that is commonly observed in patients with hereditary motor and sensory neuropathy type Ia (HMSNIa, 17p11.2–p12). Therefore, the gene for peripheral myelin protein 22 (PMP-22) is a candidate gene for both HMSNIa and HNPP. Here, we show that a similar deletion is present in one family with HNPP but is clearly absent in another family. Affected members of this family carry the expected two copies of the PMP-22 gene and the surrounding region. Furthermore, linkage analyses of this family exclude a large part of 17p, spanning the area deleted in other families with HNPP, as the location for the disease gene. These data strongly argue for the existence of genetic heterogeneity underlying HNPP. Results from two-point linkage analysis with markers on chromosome 1q are inconsistent with a possible involvement of the locus for HMSNIb in the present family.

Localization of the gene (or genes) for a syndrome with X-linked mental retardation, ataxia, weakness, hearing impairment, loss of vision and a fatal course in early childhood

Linkage analysis is described in a family with X-linked mental retardation, ataxia, weakness, floppiness, delayed motor development, absence of deep tendon reflexes, hearing impairment and loss of vision (MIM no. 301835). The disease has a fatal course due to the susceptibility of the patients to infections, especially of the respiratory tract. Clinical signs indicate impairment of the posterior columns, peripheral motor and sensory neurons and the second and eighth cranial nerves and/or their nuclei. The involvement of the posterior columns of the spinal cord is further suggested by the almost complete absence of myelinated fibers therein. We localized the responsible gene(s) to Xq21.33–q24 between DXS1231 and DXS1001 with a maximum lod score of 6.97. The proteolipid protein gene, which codes for two myelin proteins of the central nervous system and is located in this region, was considered as a candidate gene for this disorder. However, no mutations were found in the protein-coding part of this gene.

The MAS proto-oncogene is not imprinted in humans

Recently it was shown that the murine Mas gene, which is located less than 300 kb from the imprinted Igf2r gene, is also imprinted in Day 11.5 embryos with expression exclusively from the paternal allele. We have assigned the human MAS gene to chromosomal bands 6q25.3-q26 in close proximity to the IGF2R gene. In contrast to its murine homologue, the human IGF2R gene is not imprinted. By making use of a novel intragenic polymorphism, we have studied the expression of the MAS gene in three heterozygous human fetuses. In all tissues examined, including tongue, biallelic expression of the MAS gene was observed. Hence both MAS and the neighboring IGF2R gene are not imprinted in humans.

Detailed mapping, mutation analysis, and intragenic polymorphism identification in candidate Noonan syndrome genes MYL2, DCN, EPS8, and RPL6.

Editor—Noonan syndrome (NS) is an autosomal dominant developmental disorder in which the cardinal features include short stature, typical facies with hypertelorism, ptosis, downward slanting palpebral fissures, and low set, posteriorly rotated ears. In addition, there is a notable cardiac involvement seen in these patients, principally pulmonary valve stenosis and hypertrophic obstructive cardiomyopathy.1 2 The frequency of NS has been estimated to be between 1:1000-1:2500 live births.2 3 Using linkage analysis in a large three generation pedigree, we have previously mapped a gene for NS to an interval of more than 6 cM on 12q24 flanked by the markers D12S1637 and NOS1 .4 5 A similar analysis in smaller two generation families showed genetic heterogeneity for this disorder.4 Despite the relatively high incidence of NS, there appears to be a distinct lack of large families suitable for linkage analysis, possibly resulting from an increase of infertility in males.6 However, the location of the NS gene has recently been further refined to a 5 cM interval through the identification of additional recombinants in one additional large NS family.7 No chromosome rearrangements associated with the disease have so far been discovered. In view of this, one approach currently being used to identify the underlying gene responsible for this disorder is examination of candidate genes from within this large region of chromosome 12. We present below the examination of four candidate genes, the precise localisation of three of which, epidermal growth factor receptor pathway substrate-8 ( EPS8 ), decorin ( DCN ), and myosin light chain 2 ( MYL2 ), had not previously been accurately determined. The fourth, ribosomal protein L6 ( RPL6 ) was known to lie within the NS interval on 12q24.8 PCR was used to produce gene specific products for FISH (see below) and to produce exonic fragments for SSCP …

A new X linked neurodegenerative syndrome with mental retardation, blindness, convulsions, spasticity, mild hypomyelination, and early death maps to the pericentromeric region

We report on a family with an X linked neurodegenerative disorder consisting of mental retardation, blindness, convulsions, spasticity, and early death. Neuropathological examination showed mild hypomyelination. By linkage analysis, the underlying genetic defect could be assigned to the pericentromeric region of the X chromosome with a maximum lod score of 3.30 at θ=0.0 for the DXS1204 locus with DXS337 and PGK1P1 as flanking markers.