Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness.

The locus for autosomal dominant congenital stationary night blindness (adCSNB) has recently been assigned to distal chromosome 4p by linkage analysis in a large Danish family. Within the candidate gene encoding the beta-subunit of rod photoreceptor cGMP-specific phosphodiesterase (beta PDE), we have identified a heterozygous C to A transversion in exon 4, predicting a His258Asp change in the polypeptide. We found a perfect cosegregation (Zmax = 22.6 at theta = 0.00) of this mutation with the disease phenotype suggesting that this missense mutation is responsible for the disease in this pedigree. Homozygous nonsense mutations in the beta PDE gene have been found recently in patients with autosomal recessive retinitis pigmentosa, a common hereditary photoreceptor dystrophy.

Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa.

Mutation of a receptor tyrosine kinase gene, Mertk, in the Royal College of Surgeons (RCS) rat results in defective phagocytosis of photoreceptor outer segments by the retinal pigment epithelium (RPE) and retinal degeneration. We screened the human orthologue, MERTK, located at 2q14.1 (ref. 10), in 328 DNA samples from individuals with various retinal dystrophies and found three mutations in three individuals with retinitis pigmentosa (RP). Our findings are the first conclusive evidence implicating the RPE phagocytosis pathway in human retinal disease.

Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation.

X-linked forms of mental retardation (XLMR) include a variety of different disorders and may account for up to 25% of all inherited cases of mental retardation. So far, seven X-chromosomal genes mutated in nonspecific mental retardation (MRX) have been identified: FMR2, GDI1, RPS6KA3, IL1RAPL, TM4SF2, OPHN1 and PAK3 (refs 2-9). The products of the latter two have been implicated in regulation of neural plasticity by controlling the activity of small GTPases of the Rho family. Here we report the identification of a new MRX gene, ARHGEF6 (also known as alphaPIX or Cool-2), encoding a protein with homology to guanine nucleotide exchange factors for Rho GTPases (Rho GEF). Molecular analysis of a reciprocal X/21 translocation in a male with mental retardation showed that this gene in Xq26 was disrupted by the rearrangement. Mutation screening of 119 patients with nonspecific mental retardation revealed a mutation in the first intron of ARHGEF6 (IVS1-11T-->C) in all affected males in a large Dutch family. The mutation resulted in preferential skipping of exon 2, predicting a protein lacking 28 amino acids. ARHGEF6 is the eighth MRX gene identified so far and the third such gene to encode a protein that interacts with Rho GTPases.

[Hereditary cardiac amyloidosis with transthyretin mutations. A cause of sudden death ]. / Hereditäre kardiale Amyloidosen mit Mutationen des Transthyretin. Ursache des plötzlichen Todes.

Hereditary amyloidoses present a clinically and genetically heterogeneous group of autosomal dominant diseases. The most frequent form is associated with mutations of the transthyretin gene. The type of mutation determines the process, the organs primarily involved as well as the time of onset of the disease. Life expectancy is generally limited by the degree of cardiomyopathy. The cases of two male patients who died suddenly and unexpectedly are presented. In both cases, autopsy revealed a biventricular cardiac hypertrophy. Cardiac amyloidosis was diagnosed by means of histologic and genetic analysis. Early diagnosis is essential for those affected, since liver transplantation still represents the only effective treatment. This illustrates the benefit of autopsy investigations for surviving relatives, who may themselves be affected by the disease.

[Mutations of the frizzled-4 gene. Their impact on medical care of patients with autosomal dominant exudative vitreoretinopathy]. / Mutationen des frizzled-4-gens : ihre bedeutung in der betreuung von familien mit autosomal-dominanter exsudativer vitreoretinopathie.

PURPOSE: Autosomal dominant (familial) exudative vitreoretinopathy (adEVR) is a rare, congenital disease of the retinal vascular system, which may lead to blindness in severely affected eyes. One of the causative disease genes is located on chromosome 11q13-q23 and codes for "frizzled-4" (FZD4), a protein involved in vascular differentiation. METHOD: Examination of two families with adEVR over six and four generations and FZD4 mutation analysis. RESULTS: In family I, 18 examined affected members exhibited a heterozygous missense mutation (p.G492R) in the FZD4 gene. In family II, four examined family members were affected and carried a heterozygous deletion of five nucleotides (c.1286del5). Both mutations are novel and showed 100% penetrance and variable expressivity. CONCLUSIONS: With detection of the "family-specific" FZD4 gene mutation, carriers amongst offspring of affected family members can be identified at an early time. The complete penetrance of FZD4 mutations may justify abandoning repeated examinations of offspring of affected family members, if no mutations were detected in FZD4.

Mild Pelizaeus-Merzbacher disease caused by a point mutation affecting correct splicing of PLP1 mRNA.

We describe a 28-year-old male patient with a mild course of Pelizaeus-Merzbacher disease (PMD) who presented with developmental delay in his second year of life and was able to walk until 12 years of age. Several computed tomography scans in infancy and youth were normal, the diagnosis of PMD was eventually suggested by magnetic resonance imaging at the age of 24 years. Analysis of the proteolipid protein gene (PLP1) revealed a nucleotide exchange (c.762G>T) at the 3' border of exon 6, which did not entail an amino acid exchange but adversely affected splicing. PCR analysis of fibroblast cDNA showed that c.762G>T resulted in partial skipping of exon 6 in the PLP1 mRNA. Exclusion of exon 6 does not alter the reading frame but leads to absence of amino acids 232-253 that constitute a main part of the fourth transmembrane helix of the PLP protein. Remarkably, residual wild-type splicing was also detected in the patient's cultured fibroblasts. This might explain the mild phenotype in this case, as exon 6 skipping mutations resulted in a severe course of disease in other patients.

Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait.

Eight novel mutations were identified in the gene encoding L1CAM, a neural cell adhesion protein, in patients/families with X-linked hydrocephalus (XHC) providing additional evidence for extreme allelic heterogeneity of the trait. The two nonsense mutations (Gln440Ter and Gln1042Ter) result most likely in functional null-alleles and complete absence of L1CAM at the cell surface. The four missense mutations (Leu482Pro, Ser542Pro, Met741Thr, and Val752Met) as well as delSer526 may considerably alter the structure of L1CAM. Interestingly, a missense mutation in an XHC family predicting the Val768Ile change in the second fibronectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients. Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant. If this were indeed the case, our data suggest that the XHC in this family is not due to a mutation of the L1CAM gene, i.e., that, in addition to the extreme allelic heterogeneity of XHC, a non-allelic form of genetic heterogeneity may also exist in this trait.

New X-linked mental retardation syndrome with the gene mapped tentatively in Xp22.3.

X-linked mental retardation (XLMR) is genetically heterogeneous and clinically variable. We describe a new XLMR syndrome of severe mental retardation and multiple congenital anomalies. Two sisters have (with 3 different partners) 3 severely handicapped sons. In 2 cases, oligohydramnios and intrauterine growth retardation were noted. Common anomalies included a square-shaped face, high and broad forehead, frontal bossing, downward slant of palpebral fissures, hypertelorism, epicanthic folds, long philtrum, thin upper lip, and apparently low-set ears. One boy has bilateral microphthalmos and sclerocornea, and his cousin has atrophy of the optic nerve. All 3 patients are blind and have profound statomotor and mental retardation, seizures, and a grossly abnormal electroencephalographic pattern. Additional findings are short stature, delayed bone maturation, hydronephrosis, vesicorenal reflux, cryptorchidism, clinodactyly of the 5th fingers, and transverse palmar creases. The karyotype is normal (46,XY). Segregation analysis showed perfect coinheritance between the clinical phenotype and alleles at several loci in Xp22.3, whereas recombinants were identified with marker loci from Xp22.2-qter. Analysis of multiple informative meioses suggests that the disease locus maps in Xp22.3 distal to DXS16.

Short stature in a mother and daughter with terminal deletion of Xp22.3.

Short stature in females is often caused by hemizygosity for the terminal portion of Xp due to monosomy X or a deletion. We report on a mother and daughter with short stature as sole phenotypic abnormality and deletion of bands Xp22.32-p22.33 demonstrated by classic and molecular cytogenetic analysis. In both individuals, the deleted X chromosome was late replicating. Molecular analysis suggested that the deletion is terminal and the breakpoint was localized between the STS and DXS7470 loci in Xp22.32. Chromosome analysis is often done on females with short stature to exclude Ullrich-Turner syndrome. Small deletions, terminal or interstitial, are easily missed by conventional cytogenetic investigation; thus molecular analyses are useful to detect those cases.

Gene for Simpson-Golabi-Behmel syndrome is linked to HPRT in Xq26 in two European families.

Linkage analysis was performed in 2 previously described European families segregating for the Simpson-Golabi-Behmel (SGB) syndrome. In both kindreds close linkage without recombination (zmax = 4.45 at theta = 0.00) was observed between the disease locus and the HPRT locus mapped in Xq26. These data are very similar to those (zmax = 7.5 at theta = 0.00) reported recently by others after studying a large Dutch-Canadian kindred with SGB syndrome. Compiled lod scores from the 3 families reach their maximum of 11.95 at recombination fraction of 0.00 with one lod unit support interval of 0.00-0.04.

Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome: clinical and neuropathological observations in a 33-year-old man.

The syndrome of ichthyosis follicularis, alopecia, and photophobia (IFAP) is an uncommon neuroichthyosis described in only 10 males so far. We report on a man with congenital ichthyosis and alopecia with apparently normal development in early infancy. Photophobia and generalized myoclonicastatic seizures began during or after the first year of age and were associated with progressive impairment of motor skills and mental abilities. He died at 33 years of age. Neuropathological findings showed an unusual deformation of the temporal lobes and olivocerebellar atrophy. Cytogenetic and molecular studies did not uncover deletions in either Xp22.2 to 3 or in Xq27.3 to qter.

A kinematic analysis of anticipatory coarticulation in the speech of anterior aphasic subjects using electromagnetic articulography.

An investigation was made into the extent and time course of anticipatory coarticulation in the speech of two normal and two anterior aphasic, German-speaking subjects. Both labial and velar coarticulation gestures were investigated. Subjects produced sentences containing target words contrasting in postconsonantal vowel rounding (e.g., [geli:ge]/[gely:gel]) and in nasality (e.g., [ti:de]/[ti:ne]). Speech kinematics were monitored by means of electromagnetic articulography. The data revealed that for correct productions, aphasic speakers' coarticulatory patterns were more highly variable than those of control subjects. These differences, however, were found chiefly for spatial displacement characteristics, while the temporal aspects of articulator movement necessary for anticipatory coarticulation appeared largely intact. Articulator mistiming did not appear to explain a small corpus of stop/nasal substitution errors produced by one of the aphasic speakers.

Comparative measurements of airway resistance.

Three different ways to calculate airway resistance with the whole body plethysmograph during spontaneous breathing and the MBC maneuver were tested on normal subjects and patients with obstructive airway disease. The 'effective resistance values' calculated by applying periodic electric current theory correlate well with a linear interpolation of the various alveolar pressure-flow loops. These apparent linear airway resistance values are as good as the procedure described by Jaeger and Otis, based on the main assumption of sinusoidal flow, to calculate airway resistance. The difficulties in assessing the ventilated lung volume, e.g. in patients with obstructive airway disease, justifies use of the 'apparent resistance values' which are easy to calculate for clinical testing.

Three novel PAX6 mutations in patients with aniridia.

AIMS: To describe mutations in the PAX6 gene in five patients with aniridia from three unrelated families. METHODS: The PAX6 gene was analysed using single stranded conformational polymorphism analysis and direct sequencing. RESULTS: In one family, three individuals from two generations had aniridia, whereas in each of the other families only one member was affected. The first patient had the heterozygous Q221X (1023C --> T) nonsense mutation in exon 8. The same mutation was found in his mother and sister. Another patient had a heterozygous Q297X (1252C --> T) mutation in exon 10. The third patient carried a heterozygous IVS5+2T --> C mutation leading to aberrant splicing of mRNA. CONCLUSIONS: These findings provide further examples of haploinsufficiency of PAX6 in aniridia.

Missense mutation (R15W) of the connexin32 gene in a family with X chromosomal Charcot-Marie-Tooth neuropathy with only female family members affected.

A small family with sensorimotor neuropathy of dominant inheritance was examined. All three affected members were female. They had unusually severe symptoms and pronounced reduction of motor nerve conduction velocities with absent sensory nerve action potentials. Molecular genetic analysis disclosed a missense mutation in the connexin32 gene in codon 15 (Arg15Trp) which predicts the replacement of a basic amino acid to a non-polar amino acid in the first cytoplasmic loop of the protein. This report illustrates that in small pedigrees in which only women are affected, and which show a severe clinical phenotype, X chromosomal Charcot-Marie-Tooth neuropathy should be considered as differential diagnosis.

[X-chromosomal hereditary night blindness: detection of carriers by segregation analysis with linked DNA markers]. / X-chromosomal erbliche Nachtblindheit: Erkennen von Uberträgerinnen durch Segregationsanalyse mit gekoppelten DNA-Markern.

Congenital stationary night blindness is a rare disease with autosomal dominant, autosomal recessive, or X-linked recessive inheritance. The X-chromosomal form is frequently associated with myopia. Female carriers have no symptoms of visual impairment and therefore cannot be identified clinically. The close link recently described between the disease locus and the DXS7 locus, mapped in Xp11.3, as well as other marker loci from this chromosomal region, permits indirect genotype analysis and thus identification of the carriers; with the information thus obtained, improved genetic counseling is possible. The authors studied a large Swiss family with the X-linked trait. Segregation analysis was performed with DXS7 as well as two flanking markers, DXS255 and OTC. It was thus possible to determine the degree or probability of several female members of the family being carriers.

[Indirect genotype analysis as a diagnostic procedure in Marfan syndrome]. / Die indirekte Genotypanalyse als diagnostisches Verfahren beim Marfan-Syndrom.

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue characterized by skeletal, ocular and cardiovascular manifestations. The disease is caused by mutations in the FBN1 gene, encoding fibrillin, an important component of elastic fibers. Diagnosis of Marfan syndrome is currently based on detailed clinical examination and/or mutation analysis in the fibrillin gene. Clinical expression varies widely both among and within families, rendering clinical diagnosis extremely difficult. In this study, we performed segregation analysis of allelic DNA polymorphisms to support diagnosis of Marfan syndrome. This type of genotype analysis is a useful, additional diagnostic tool for families with Marfan syndrome and provides incremental information of diagnosis or exclusion of Marfan syndrome based on clinical findings.

A Y/5 translocation in a 45,X male with cri du chat syndrome.

In a patient described as a 45,X male with cri du chat syndrome, combined cytogenetic and molecular methods revealed Y euchromatic material to be translocated onto the short arm of one chromosome 5, resulting in a chromosome der(5)(5qter----5p14::Yp11.31----Ypter). The translocated Y euchromatin comprised only the distal short arm including the pseudoautosomal region and the so-called deletion intervals 1 and 2. A review of 45,X males from the literature showed that; most of them carry a paternally transmitted Y/autosome translocations; resulting in various autosomal deletions. Depending on the segment concerned, the deletion led to congenital malformations.