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- Arnell, Henrik, et al.
(författare)
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The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q
- 1997
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 34:5, s. 360-5
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Tidskriftsartikel (refereegranskat)abstract
- Primary nocturnal enuresis (PNE), or bedwetting at night, affects approximately 10% of 6 year old children. Genetic components contribute to the pathogenesis and recently one locus was assigned to chromosome 13q. We evaluated the genetic factors and the pattern of inheritance for PNE in 392 families. Dominant transmission was observed in 43% and an apparent recessive mode of inheritance was observed in 9% of the families. Among the 392 probands the ratio of males to females was 3:1 indicating sex linked or sex influenced factors. Linkage to candidate regions was tested in 16 larger families segregating for autosomal dominant PNE. A gene for PNE was excluded from chromosome 13q in 11 families, whereas linkage to the interval D13S263-D13S291 was suggested (Zmax = 2.1) in three families. Further linkage analyses excluded about 1/3 of the genome at a 10 cM resolution except the region around D12S80 on chromosome 12q that showed a positive two point lod score in six of the families (Zmax = 4.2). This locus remains suggestive because the material was not sufficiently large to give evidence for heterogeneity. Our pedigree analysis indicates that major genes are involved in a large proportion of PNE families and the linkage results suggest that such a gene is located on chromosome 12q.
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| 5. |
- Celse, Tristan, et al.
(författare)
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OTX2 duplications : a recurrent cause of oculo-auriculo-vertebral spectrum
- 2023
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Ingår i: Journal of Medical Genetics. - : BMJ Publishing Group Ltd. - 0022-2593 .- 1468-6244. ; 60:6, s. 620-626
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Tidskriftsartikel (refereegranskat)abstract
- Background Oculo-auriculo-vertebral spectrum (OAVS) is the second most common cause of head and neck malformations in children after orofacial clefts. OAVS is clinically heterogeneous and characterised by a broad range of clinical features including ear anomalies with or without hearing loss, hemifacial microsomia, orofacial clefts, ocular defects and vertebral abnormalities. Various genetic causes were associated with OAVS and copy number variations represent a recurrent cause of OAVS, but the responsible gene often remains elusive.Methods We described an international cohort of 17 patients, including 10 probands and 7 affected relatives, presenting with OAVS and carrying a 14q22.3 microduplication detected using chromosomal microarray analysis. For each patient, clinical data were collected using a detailed questionnaire addressed to the referring clinicians. We subsequently studied the effects of OTX2 overexpression in a zebrafish model.Results We defined a 272 kb minimal common region that only overlaps with the OTX2 gene. Head and face defects with a predominance of ear malformations were present in 100% of patients. The variability in expressivity was significant, ranging from simple chondromas to severe microtia, even between intrafamilial cases. Heterologous overexpression of OTX2 in zebrafish embryos showed significant effects on early development with alterations in craniofacial development.Conclusions Our results indicate that proper OTX2 dosage seems to be critical for the normal development of the first and second branchial arches. Overall, we demonstrated that OTX2 genomic duplications are a recurrent cause of OAVS marked by auricular malformations of variable severity.
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| 6. |
- Dahlqvist, Johanna, et al.
(författare)
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Congenital ichthyosis : mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis
- 2007
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 44:10, s. 615-620
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Tidskriftsartikel (refereegranskat)abstract
- Background: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin disorders. Several mutant genes have been identified in ARCI, but the association between genotype and phenotype is poorly understood. Methods: To investigate genotype–phenotype correlations in ARCI, we selected 27 patients from 18 families with specific ultrastructural features of the epidermis. The characteristic findings using electron microscopy (EM) were abnormal lamellar bodies and elongated membranes in the stratum granulosum, classified as ARCI EM type III. DNA samples from a subset of affected individuals were screened for homozygous genomic regions, and a candidate gene region was identified on chromosome 5q33. The region coincides with the ichthyin gene, previously reported as mutated in ARCI. Results: Mutation screening of ichthyin revealed missense or splice-site mutations in affected members from 16 of 18 (89%) families with characteristics of ARCI EM type III. In a control group of 18 patients with ARCI without EM findings consistent with type III, we identified one patient homozygous for a missense mutation in ichthyin. Discussion: Our findings indicate a strong association between ultrastructural abnormalities in the granular layer of epidermis and ichthyin mutations. The results also suggest that EM provides a tool for specific diagnosis in a genetically homogenous subgroup of patients with ARCI.
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| 8. |
- Dhanraj, Santhosh, et al.
(författare)
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Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)
- 2015
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 52:11, s. 738-748
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Tidskriftsartikel (refereegranskat)abstract
- Background Deadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease (PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biological significance of germline mutations in PARN. Methods We identified mutations in PARN in patients with haematological and neurological manifestations. Genomic, biochemical and knockdown experiments in human marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease. Results We identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination and bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patient had impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficient patient cells manifested short telomeres and an aberrant ribosome profile similar to those described in some variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafish impaired haematopoiesis, providing further evidence for a causal link with the human disease. Conclusions Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.
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