https://www.kidney-international.org/article/S0085-2538(15)33410-4/pdf

Genetic heterogeneity of Alport syndrome.

Transcriptional arrest caused by DNA damage is detrimental for cells and organisms as it impinges on gene expression and thereby on cell growth and survival. To alleviate transcriptional arrest, cells trigger a transcription-dependent genome surveillance pathway, termed transcription-coupled nucleotide excision repair (TC-NER) that ensures rapid removal of such transcription-impeding DNA lesions and prevents persistent stalling of transcription. Defective TC-NER is causatively linked to Cockayne syndrome, a rare severe genetic disorder with multisystem abnormalities that results in patients' death in early adulthood. Here we review recent data on how damage-arrested transcription is actively coupled to TC-NER in mammals and discuss new emerging models concerning the role of TC-NER-specific factors in this process.

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Mammalian Transcription-Coupled Excision Repair

The Brachmann-de Lange syndrome.

Five X-chromosome DNA markers were typed on 261 members of three large kindreds with Alport syndrome (hereditary glomerulonephritis). Lod scores greater than 3.0 for linkage between the disease locus and two of the markers confirmed X-linked inheritance of the disease. A decreasing gradient in the estimated recombination fractions observed when the markers were ordered on the basis of their map locations suggested that the disease locus is on the long arm distal to all the markers typed in this study. Using three-locus analysis we rejected all but three map orders for the six loci (the disease locus and five markers). In all three the Alport syndrome locus was on the long arm of the X chromosome distal to all the markers. Two types of Alport syndrome were represented in the three kindreds. Affected males in one kindred developed deafness in addition to nephritis; deafness did not occur in members of the other two kindreds. Although larger recombination-fraction estimates were obtained for all five markers in the kindreds without deafness, the difference was significant for only one marker. Evidence of heterogeneity was not found in tests using two markers. Markers distal to the disease locus are needed to determine whether two loci are responsible for the two types of Alport syndrome.

Mapping of Alport syndrome to the long arm of the X chromosome.

Cerebro-oculo-facio-skeletal (COFS) syndrome is a recessively inherited rapidly progressive neurologic disorder leading to brain atrophy, with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure Cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low to normal birth weight, growth failure, brain dysmyelination with calcium deposits, cutaneous photosensitivity, pigmentary retinopathy and/or cataracts, and sensorineural hearing loss Cultured CS cells are hypersensitive to UV radiation, because of impaired nucleotide-excision repair (NER) of UV-induced damage in actively transcribed DNA, whereas global genome NER is unaffected The abnormalities in CS are caused by mutated CSA or CSB genes Another class of patients with CS symptoms have mutations in the XPB, XPD, or XPG genes, which result in UV hypersensitivity as well as defective global NER; such patients may concurrently have clinical features of another NER syndrome, xeroderma pigmentosum (XP) Clinically observed similarities between COFS syndrome and CS have been followed by discoveries of cases of COFS syndrome that are associated with mutations in the XPG and CSB genes Here we report the first involvement of the XPD gene in a new case of UV-sensitive COFS syndrome, with heterozygous substitutions—a R616W null mutation (previously seen in patients in XP complementation group D) and a unique D681N mutation—demonstrating that a third gene can be involved in COFS syndrome We propose that COFS syndrome be included within the already known spectrum of NER disorders: XP, CS, and trichothiodystrophy We predict that future patients with COFS syndrome will be found to have mutations in the CSA or XPB genes, and we document successful use of DNA repair for prenatal diagnosis in triplet and singleton pregnancies at risk for COFS syndrome This result strongly underlines the need for screening of patients with COFS syndrome, for either UV sensitivity or DNA-repair abnormalities

Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy.

A patient with the lobster claw defect, ectodermal defect, and tear duct and renal anomalies is described. An argument is presented for grouping this patient with other patients with lobster claw defect, ectodermal defects and tear duct anomalies who also have cleft lip-palate and are classified as having the EEC syndrome

The lobster claw defect with ectodermal defects, cleft lip-palate, tear duct anomaly and renal anomalies.

A patient with the Cerebro-Oculo-Facio-Skeletal syndrome is described. The phenotype of the syndrome has been extended somewhat and autosomal recessive inheritance further supported by the finding of parental consanguinity.

The cerebro-oculo-facio-skeletal syndrome.

The inheritance of Alport's disease, hereditary nephropathy with deafness, has been re–examined using data from a large French–Canadian kindred and reports from the literature. Sibships in wliich a parent and grandparent were known to carry the gene were used to test for partial sex–linkage. A decrease, rather than the expected increase, in affected sons of affected males with an affected father makes this hypothesis untenable. No matter which grandparent was affected, mothers with the gene had equal numbers of affected and unaffected offspring of both sexes, as expected for autosomal dominant inheritance; fathers with the gene had a decrease from the expected proportion of affected sons and an increase in unaffected sons with no distortion of the sex ratio. The hypotheses of preferential segregation and of a sex–linked dominant modifier gene have likewise been discredited. The findings fit the expectation for autosomal dominant inheritance, with reduced penetrance in the sons of affected fathers; it is suggested that the unfavourable intrauterine milieu of the affected mother increases the penetrance of the gene in her sons to that in her daughters. This is supported by a lower frequency of affected offspring from asymptomatic than from symptomatic carrier mothers. The puzzle remains as to why there is a more serious disease, yet reduced penetrance in the males. Figures appropriate for genetic counselling are provided.

Genetics of hereditary nephropathy with deafness (Alport's disease).

Three trisomic offspring conceived by artificial insemination by donor (AID) were observed in a population in which a total of about 400 babies were so conceived To test whether this excess represented a random fluctuation or a real effect of the AID procedure we surveyed, by questionnaire, a group of women who had born children conceived by AID A significantly higher number of trisomic offspring were found than expected in a population with the observed age distribution Further data are needed to test the validity of this observation

Possible teratogenic effects of artificial insemination by donor.

A method has been developed to test for heterogeneity in syndromes of unknown etiology and to distinguish between patients with and without the syndrome. The validity of the method was tested on a group of patients suspected of having a syndrome that can be diagnosed by other means (Down syndrome), and was found to be effective. The method was then applied to a group of patients suspected of having a syndrome of unknown etiology (de Lange). It was shown that the group appears to be heterogeneous. A preliminary diagnosis of having or not having the syndrome was made in about 80 % of the patients.

F. C. Fraser

Papers

The lobster claw defect with ectodermal defects, cleft lip-palate, tear duct anomaly and renal anomalies.

The cerebro-oculo-facio-skeletal syndrome.

Genetics of hereditary nephropathy with deafness (Alport's disease).

Possible teratogenic effects of artificial insemination by donor.

A methodology for establishing a diagnostic index for syndromes of unknown etiology.