<i>KCTD1</i> and Scalp-Ear-Nipple (‘Finlay–Marks’) syndrome may be associated with myopia and Thin basement membrane nephropathy through an effect on the collagen IV α3 and α4 chains

Wang, Dongmao; Trevillian, Paul; May, Stephen; Diakumis, Peter; Wang, Yanyan; Colville, Deb; Bahlo, Melanie; Greferath, Ursula; Fletcher, Erica L.; Young, Brian J.; Mack, Heather G; Savige, Judy

doi:10.1080/13816810.2022.2144900

Cited by 4 publications

(3 citation statements)

References 41 publications

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“…A comprehensive understanding of the in vivo functions of KCTD1 is lacking. Heterozygous missense mutations in KCTD1 lead to autosomal dominant scalp-ear-nipple (SEN) syndrome, which manifests primarily with scalp ACC, various additional ectodermal abnormalities (sparse hair, absence of incisors, anhidrosis, hypoplasia or absence of nipples/breasts), and facial dysmorphism, as well as progressive renal fibrosis (7,10,11). KCTD1 represses the transactivation of the transcription factor AP-2α through binding via its BTB domain, and KCTD1 mutations in SEN syndrome abrogate the binding and inhibitory activity of KCTD1 on AP-2α, resulting in increased transcriptional activity of AP-2α (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis

Raymundo,

Zhang,

Smaldone

et al. 2023

Journal of Clinical Investigation

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Aplasia cutis congenita (ACC) is a congenital epidermal defect of the midline scalp and has been proposed to be due to a primary keratinocyte abnormality. Why it forms mainly at this anatomic site has remained a long-standing enigma. KCTD1 mutations cause ACC, ectodermal abnormalities, and kidney fibrosis, whereas KCTD15 mutations cause ACC and cardiac outflow tract abnormalities. Here, we found that KCTD1 and KCTD15 can form multimeric complexes and can compensate for each other’s loss and that disease mutations are dominant negative, resulting in lack of KCTD1/KCTD15 function. We demonstrated that KCTD15 is critical for cardiac outflow tract development, whereas KCTD1 regulates distal nephron function. Combined inactivation of KCTD1/KCTD15 in keratinocytes resulted in abnormal skin appendages but not in ACC. Instead, KCTD1/KCTD15 inactivation in neural crest cells resulted in ACC linked to midline skull defects, demonstrating that ACC is not caused by a primary defect in keratinocytes but is a secondary consequence of impaired cranial neural crest cells, giving rise to midline cranial suture cells that express keratinocyte-promoting growth factors. Our findings explain the clinical observations in patients with KCTD1 versus KCTD15 mutations, establish KCTD1/KCTD15 complexes as critical regulators of ectodermal and neural crest cell functions, and define ACC as a neurocristopathy.

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Section: Introductionmentioning

confidence: 99%

KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis

Raymundo,

Zhang,

Smaldone

et al. 2023

Journal of Clinical Investigation

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“…KCTD proteins constitute an emerging class of proteins involved in severe and widespread pathologies that include cancer [6], neurological disorders [5], and genetic diseases [20,46,76,[90][91][92][93][94][95][96][97][98][99]. The BTB domain located in the N-terminal region of all these proteins constitutes the defining element of the family.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3

Balasco,

Esposito,

Smaldone

et al. 2024

IJMS

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KCTD ((K)potassium Channel Tetramerization Domain-containing) proteins constitute an emerging class of proteins involved in fundamental physio-pathological processes. In these proteins, the BTB domain, which represents the defining element of the family, may have the dual role of promoting oligomerization and favoring functionally important partnerships with different interactors. Here, by exploiting the potential of recently developed methodologies for protein structure prediction, we report a comprehensive analysis of the interactions of all KCTD proteins with their most common partner Cullin 3 (Cul3). The data here presented demonstrate the impressive ability of this approach to discriminate between KCTDs that interact with Cul3 and those that do not. Indeed, reliable and stable models of the complexes were only obtained for the 15 members of the family that are known to interact with Cul3. The generation of three-dimensional models for all KCTD–Cul3 complexes provides interesting clues on the determinants of the structural basis of this partnership as clear structural differences emerged between KCTDs that bind or do not bind Cul3. Finally, the availability of accurate three-dimensional models for KCTD–Cul3 interactions may be valuable for the ad hoc design and development of compounds targeting specific KCTDs that are involved in several common diseases.

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“…This was formerly named, and is still used by some, as thin basement membrane nephropathy (TBMN). Also, a thin GBM lesion and microscopic hematuria may be caused by mutations in other genes [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice

Deltas,

Papagregoriou,

Louka

et al. 2023

Genes

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Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, COL4A3/A4/A5. Pathogenic variants in COL4A5 are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the COL4A3 or the COL4A4 gene cause autosomal recessive AS. AS usually leads to progressive kidney failure before the age of 40-years when left untreated. People who inherit heterozygous COL4A3/A4 variants are at-risk of a slowly progressive form of the disease, starting with microscopic hematuria in early childhood, developing Alport spectrum nephropathy. Sometimes, they are diagnosed with benign familial hematuria, and sometimes with autosomal dominant AS. At diagnosis, they often show thin basement membrane nephropathy, reflecting the uniform thin glomerular basement membrane lesion, inherited as an autosomal dominant condition. On a long follow-up, most patients will retain normal or mildly affected kidney function, while a substantial proportion will develop chronic kidney disease (CKD), even kidney failure at an average age of 55-years. A question that remains unanswered is how to distinguish those patients with AS or with heterozygous COL4A3/A4 variants who will manifest a more aggressive kidney function decline, requiring prompt medical intervention. The hypothesis that a subgroup of patients coinherit additional genetic modifiers that exacerbate their clinical course has been investigated by several researchers. Here, we review all publications that describe the potential role of candidate genetic modifiers in patients and include a summary of studies in AS mouse models.

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KCTD1 and Scalp-Ear-Nipple (‘Finlay–Marks’) syndrome may be associated with myopia and Thin basement membrane nephropathy through an effect on the collagen IV α3 and α4 chains

Cited by 4 publications

References 41 publications

KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis

KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions, and their impairment causes aplasia cutis

A Comprehensive Analysis of the Structural Recognition between KCTD Proteins and Cullin 3

Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice

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