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Genetics of Uterine Leiomyomata
Published in John C. Petrozza, Uterine Fibroids, 2020
C. Scott Gallagher, Cynthia C. Morton
Alport syndrome with diffuse leiomyomatosis (AS-DL) is an X-linked-dominant, hereditary nephropathy associated with development of leiomyomata in the esophagus, tracheobronchial tree and genital tract [77–79]. Disease phenotypes observed in both AS and AS-DL are a consequence of abnormal basement membranes resulting from improper assembly of collagen IV protomers [80,81]. COL4A5 (collagen type IV alpha 5) and COL4A6 (collagen type IV alpha 6) reside in a head-to-head orientation on the X chromosome, and AS-DL is associated specifically with deletions spanning from the 5′ region of COL4A5 into the 5′ region of COL4A6 [78,79,82–84]. Of note, null mutations in the 5′ end of COL4A5 that do not extend into COL4A6 are sufficient to cause AS but insufficient to cause AS-DL [78,85]. WGS of isolated cases of UL without AS-DL have detected somatic deletions and rearrangements in the COL4A5-COL4A6 locus, further supporting a role for the two collagen type IV alpha chains in development and growth of UL [7,53].
Genetics in Otology and Neurotology
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Progressive sensorineural hearing loss, renal disorder (glomerulonephritis, haematuria, renal failure) and eye problems (lenticular and macular abnormalities) are observed. Almost 50% develop progressive bilateral hearing loss, which usually begins in the second decade.30 This syndrome is X-linked in 85%, autosomal recessive in 15% and autosomal dominant in the remainders. In the X-linked form, males are more severely affected than females. The COL4A5 gene on Xq22 and the COL4A3 and COL4A4 genes on chromosome 2q36–q37 are responsible for the syndrome.30
Anatomy of the Cochlea and Vestibular System: Relating Ultrastructure to Function
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
The basilar membrane (BM) is a sheet formed predominantly of extracellular matrix (Figure 47.4b,c and 47.7n). It is composed of filaments within a ground substance, with a discontinuous layer of thin, elongated tympanic border cells on the underside facing the perilymph of the scala tympani.17 The fibrils of the BM run predominantly radially, and are composed of collagen, mostly collagen type IV ±1–±5 chains (COL4A1–COL4A5).78 In addition, fibronectin79 and laminin type 11,80 adhesive-type molecules common to extracellular matrices, are localized to the BM and presumably compose the ground substance in which the collagen fibrils reside. The composition of the BM does not appear to be unique in comparison with basement membranes elsewhere in the body, except for a novel extracellular matrix protein (named ‘usherin’)38,81 that has been identified through the genetic mutation which is associated with Usher syndrome type 2A, in which there is high-frequency hearing loss. Mutations in the genes for the proteins composing the BM might be expected to affect the mechanics of the organ of Corti in response to sound and thereby cause hearing impairment. X-linked Alport syndrome has been attributed to mutations in the COL4A5 gene. It has been suggested that it is the loss of this protein from the BM that results in the high frequency hearing loss associated with this condition.82
Ultrastructural and immunofluorescence analysis of anterior lens capsules in autosomal recessive Alport syndrome
Published in Ophthalmic Genetics, 2021
Jiayue Zhou, Jing Wu, Qichuan Yin, Xiaoning Yu, Yilei Cui, Hao Yang, Xingchao Shentu
Mutations in the COL4A3, COL4A4 (6), and COL4A5 (7) genes encoding α3, α4, and α5 chains of type Ⅳ collagen, respectively, are responsible for the Alport syndrome. There are six different types of collagen α chains forming three forms of type Ⅳ collagen heterotrimers (8). The heterotrimers comprised of α1(Ⅳ)/α1(Ⅳ)/α2(Ⅳ), α3(Ⅳ)/α4(Ⅳ)/α5(Ⅳ), and α5(Ⅳ)/α5(Ⅳ)/α6(Ⅳ) then form distinct type Ⅳ collagen networks in basement membranes (8). The α1(Ⅳ)/α1(Ⅳ)/α2(Ⅳ) network is the most widespread basement membrane component (9), whereas the α3(Ⅳ)/α4(Ⅳ)/α5(Ⅳ) network is mainly distributed in adult glomerular basement membrane, cochlea (stria vascularis), cornea (Descemet’s and Bowman’s membranes), lens capsule, and retina (inner limiting membrane and Bruch’s membrane). The α5(Ⅳ)/α5(Ⅳ)/α6(Ⅳ) network exists in skin (10). According to the inheritance pattern and mutated genes, the syndrome can be divided into three types: approximately 80%-85% of cases are classified as X-linked Alport syndrome 1 (XLAS) caused by COL4A5 mutations, 10%-15% are classified as autosomal recessive Alport syndrome 2 (ARAS) caused by COL4A3 or COL4A4 mutations, and less than 5% are classified as autosomal dominant Alport syndrome 3 (ADAS) caused by COL4A3 mutations (11).
The role of discoidin domain receptor 2 in the renal dysfunction of alport syndrome mouse model
Published in Renal Failure, 2021
Yuya Sannomiya, Shota Kaseda, Misato Kamura, Hiroshi Yamamoto, Hiroyuki Yamada, Masataka Inamoto, Jun Kuwazuru, Saki Niino, Tsuyoshi Shuto, Mary Ann Suico, Hirofumi Kai
Alport syndrome (AS) is a hereditary disease that causes progressive loss of kidney function. It is caused by a mutation in one of the type IV collagen genes that code for COL4A3, COL4A4, and COL4A5 proteins. These type IV collagens form protomer network that are important components of the glomerular basement membrane (GBM). Mutations in type IV collagen genes disrupt the structure and function of GBM [1,2]. Abnormal GBM structure interferes with the glomerular filtration system leading to proteinuria, inflammation, renal fibrosis and finally to end-stage renal disease (ESRD). Currently, renin angiotensin aldosterone system (RAAS) inhibitors are used for AS therapy. Although early treatment with RAAS inhibitor delays renal failure in AS patients, the disease eventually progresses into ESRD [3,4]. It is now generally believed that RAAS inhibitor is not sufficient for AS therapy. Therefore, it is important to continue the search for novel therapeutic targets that have different mechanism from RAAS inhibitors.
An update on current and potential genetic insights and diagnosis of Alport syndrome
Published in Expert Opinion on Orphan Drugs, 2020
In males with XLAS the risk of kidney failure, in the absence of treatment, is 100% over the course of a lifetime [18,36]. The most important determinant of age at the onset of kidney failure is COL4A5 genotype [18,36]. The COL4A5 genotype also determines the ages at which hearing loss becomes detectable and hearing aids are required, and the risk of anterior lenticonus, the pathognomonic ocular lesion of Alport syndrome [18,36]. Deletions (and other major rearrangements) and nonsense variants predict earlier onset of kidney failure and hearing loss, while missense variants are associated with onset of kidney failure and hearing loss relatively later in life [18,36]. The phenotype associated with splicing variants falls in between these two poles in terms of the pace of progression of renal and cochlear symptoms, with truncating variants resulting in more aggressive disease [18,36,37]. These genotype-phenotype correlations reflect the effect of the COL4A5 variant on the expression of the collagen IV alpha5 chain and alpha345 network in basement membranes: COL4A5 variants that prevent the expression of the collagen IV alpha5 chain, and therefore the alpha345 network, in basement membranes are associated with a severe phenotype, while variants that allow at least some expression of the collagen IV alpha5 chain and alpha345 network in basement membranes are associated with a milder phenotype [38].