A new mutation in the COL4A3 gene responsible for autosomal dominant Alport syndrome, which only generates hearing loss in some carriers

Rosado, Consolación; Bueno, Elena Villamañán; Fraile, Pilar Quijada; García-Cosmes, Pedro; González-Sarmiento, Rogelio

doi:10.1016/j.ejmg.2014.10.003

Cited by 11 publications

(16 citation statements)

References 10 publications

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“…However, our patients were diagnosed with hearing loss at an early age (before 30 years), which can be explained by the high clinical variability presented by this inheritance pattern [1]. In our series we found patients with ocular injuries, such as lenticonus, which until now had only been described in recessive and sex-linked inheritance patterns [10,14,17,20].…”

Section: Discussionmentioning

confidence: 89%

“…Instead, it can behave similarly to the recessive or X-linked disease. Until now, there is not a clear explanation for this great variability, but there are some hypothesis who affirm that mutations in other genes of the glomerular basal membrane, who encode different proteins such as laminin, podocin, integrins or metalloproteases could modulate the phenotypic expression of the COL4A3 or COL4A4 mutations in some patients, who would suffer a more severe illness, while their relatives, who only suffer the COL4A3 or COL4A4 mutations, would suffer a milder disease [10,11].…”

Section: Resultsmentioning

confidence: 99%

“…Age of onset of the different symptoms can ensure that these families suffer from autosomal dominant Alport syndrome, since we have studied the two genes and we have been able to exclude a second mutation in every patient. Besides, all the mutations responsible for the illness in our families are pathogenic mutations (frameshift, splicing and missense), described in different works [1, 10,11].…”

Section: Discussionmentioning

confidence: 99%

“…Its real prevalence is unknown, because audiometries are not common practice [18]. However, it is necessary to emphasize the importance of taking this symptom as a key factor in the diagnosis of the disease in cases of nephropathies accompanied by haematuria and proteinuria, because its presence in these cases is highly suggestive of this genetic disorder [10]. Hearing loss is observed in late infancy or adolescence in patients with recessive and X chromosome-linked patterns, whereas in the cases with a dominant inheritance pattern it appears in adult age [2,19,20].…”

Section: Discussionmentioning

confidence: 99%

“…We studied 10 patients, who shared the pathogenic mutation c.345 delG; p.G115GfsX37 in the COL4A3 gene [10]. The study of the COL4A4 gene did not show any pathogenic mutation.…”

Section: Familymentioning

confidence: 99%

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Study of the True Clinical Progression of Autosomal Dominant Alport Syndrome in a European Population

Rosado

Bueno

Felipe

et al. 2015

Kidney Blood Press Res

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Background/Aims: Autosomal dominant Alport syndrome represents 5% of all Alport syndrome cases. This entity presents a different clinical expression from the recessive inheritance pattern and the X chromosome-linked pattern, because it is mild and it shows a late onset, which in many cases even goes unnoticed. Methods: We carried out a descriptive observational and retrospective clinical study on 19 patients from 5 families with a clinical diagnosis of autosomal dominant Alport Syndrome, and we analyzed the expression of the symptoms in the different families, comparing the results with what has been described in the literature. Results: Renal involvement appeared at a young age, with a progression towards end-stage chronic kidney disease at a median age of 31 years (20.5-36.5). Hearing involvement also appeared in early stages, at a median age of 28.5 years (7.5-62.5). Also, we observed ocular lenticonus-like injuries, which until now have only been described in other inheritance patterns. Conclusions: Our results suggest that dominant patterns are accompanied by a severe clinical expression that can be superimposed to the recessive and X chromosome-linked patterns, contrary to what has been classically stated. The high phenotypic variability observed in the families lead to the fact that many cases go unnoticed and the severest cases are erroneously diagnosed as recessive, which means that the real prevalence of dominant forms is probably higher than the current 5%.

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…We studied 10 patients, who shared the pathogenic mutation c.345 delG; p.G115GfsX37 in the COL4A3 gene [10]. The study of the COL4A4 gene did not show any pathogenic mutation.…”

Section: Familymentioning

confidence: 99%

See 3 more Smart Citations

Study of the True Clinical Progression of Autosomal Dominant Alport Syndrome in a European Population

Rosado

Bueno

Felipe

et al. 2015

Kidney Blood Press Res

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Unraveling the Genetic Basis of Combined Deafness and Male Infertility Phenotypes through High‐Throughput Sequencing in a Unique Cohort from South India

Justin Margret,

Jayasankaran,

Amritkumar

et al. 2024

Advanced Genetics

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The co‐occurrence of sensorineural hearing loss and male infertility has been reported in several instances, suggesting potential shared genetic underpinnings. One such example is the contiguous gene deletion of CATSPER2 and STRC genes, previously associated with deafness‐infertility syndrome (DIS) in males. Fifteen males with both hearing loss and infertility from southern India after exclusion for the DIS contiguous gene deletion and the FOXI1 gene mutations are subjected to exome sequencing. This resolves the genetic etiology in four probands for both the phenotypes; In the remaining 11 probands, two each conclusively accounted for deafness and male infertility etiologies. Genetic heterogeneity is well reflected in both phenotypes. Four recessive (TRIOBP, SLC26A4, GJB2, COL4A3) and one dominant (SOX10) for the deafness; six recessive genes (LRGUK, DNAH9, ARMC4, DNAH2, RSPH6A, and ACE) for male infertility can be conclusively ascribed. LRGUK and RSPH6A genes are implicated earlier only in mice models, while the ARMC4 gene is implicated in chronic destructive airway diseases due to primary ciliary dyskinesia. This study would be the first to document the role of these genes in the male infertility phenotype in humans. The result suggests that deafness and infertility are independent events and do not segregate together among the probands.

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Renal, auricular, and ocular outcomes of Alport syndrome and their current management

Zhang

Ding

2017

Pediatr Nephrol

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Alport syndrome is a hereditary glomerular basement membrane disease caused by mutations in the COL4A3/4/5 genes encoding the type IV collagen alpha 3-5 chains. Most cases of Alport syndrome are inherited as X-linked dominant, and some as autosomal recessive or autosomal dominant. The primary manifestations are hematuria, proteinuria, and progressive renal failure, whereas some patients present with sensorineural hearing loss and ocular abnormalities. Renin-angiotensin-aldosterone system blockade is proven to delay the onset of renal failure by reducing proteinuria. Renal transplantation is a curative treatment for patients who have progressed to end-stage renal disease. However, only supportive measures can be used to improve hearing loss and visual loss. Although both stem cell therapy and gene therapy aim to repair the basement membrane defects, technical difficulties require more research in Alport mice before clinical studies. Here, we review the renal, auricular, and ocular manifestations and outcomes of Alport syndrome and their current management.

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A new mutation in the COL4A3 gene responsible for autosomal dominant Alport syndrome, which only generates hearing loss in some carriers

Cited by 11 publications

References 10 publications

Study of the True Clinical Progression of Autosomal Dominant Alport Syndrome in a European Population

Study of the True Clinical Progression of Autosomal Dominant Alport Syndrome in a European Population

Unraveling the Genetic Basis of Combined Deafness and Male Infertility Phenotypes through High‐Throughput Sequencing in a Unique Cohort from South India

Renal, auricular, and ocular outcomes of Alport syndrome and their current management

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