Cytogenetic location: 15q23 Genomic coordinates (GRCh38): 15:71096894-71783383 (by NCBI)
TEXT
Description
Microfibrils are multifunctional fibrillar extracellular matrices that contribute to the elastic properties of connective tissue and control the bioavailability of growth factors. THSD4 promotes microfibril assembly (Tsutsui et al., 2010).
Cloning and Expression
Tsutsui et al. (2010) cloned two mouse Thsd4 splice variants, which they named Adamtsl6-alpha and Adamtsl6-beta. The derived proteins contain 1,018 and 658 amino acids, respectively. Full-length Adamtsl6-alpha has an N-terminal signal sequence followed by an atypical thrombospondin type 1 repeat (TSR), a cysteine-rich domain, an ADAMTS spacer, 6 tandem TSRs, and a C-terminal PLAC domain. The atypical N-terminal TSR is bisected by an insertion of approximately 200 amino acids. This TSR contains a consensus tryptophan motif (WxxWxxW) and 6 conserved cysteines, and the insert contains 2 heparin binding motifs (RRxR). Adamtsl6-beta lacks the atypical N-terminal TSR and cysteine-rich domain of Adamtsl6-alpha and instead has the N-terminal signal sequence directly fused to the ADAMTS spacer. Both Adamts16 isoforms contain N-glycosylation sites. RT-PCR of mouse tissues showed ubiquitous and almost uniform expression of Adamtsl6-alpha. In contrast, Adamtsl6-beta was differentially expressed in selected tissues including brain, spinal cord, eye, kidney, stomach and uterus and was not expressed in heart, liver, lymph nodes, submandibular gland and spleen. Both variants were expressed in mouse embryos at all developmental stages tested. Immunohistochemical analysis and immunological gold microscopy of embryonic and adult mice revealed the expression of Adamtsl6 in fibrillar structures of various elastic tissues, where it was colocalized with fibrillin-1 (FBN1; 134797). Gel electrophoresis performed under reducing and non-reducing conditions suggested that Adamtsl6 could form both intramolecular and intermolecular disulfide bonds. After transfection of human osteosarcoma cells, both Adamtsl6 isoforms were recovered in the extracellular matrix, but unlike Adamtsl6-alpha, Adamtsl6-beta was also found in the conditioned medium. Adamtsl6 secretion was dependent on its N-glycosylation. Saito et al. (2011) studied the expression of Adamtsl6 during the development of embryonic tooth germs in mice. They found that Adamtsl6-beta is specifically regulated during the formation of the periodontal ligament, which consists of elastic fibers composed of fibrillin-1 microfibrils. Adamtsl6-beta expression was downregulated in the adult periodontal ligament. Adamtsl6-alpha was only expressed in odontoblasts.
Gene structure
Elbitar et al. (2021) stated that the THSD4 gene contains 17 coding exons.
cartography
Hartz (2011) assigned the THSD4 gene to chromosome 15q23 based on an alignment of the THSD4 sequence (GenBank AK023772) with the genomic sequence (GRCh37). Tsutsui et al. (2010) found that the mouse Thsd4 gene maps to chromosome 9.
Gene function
Tsutsui et al. (2010) found that recombinant mouse Adamtsl6-beta interacted with the N-terminal half of fibrillin-1 in a dose-dependent manner. When transfected into human osteosarcoma cells, both Adamtsl6-alpha and -beta promoted fibrillin-1 microfibril formation in a dose-dependent manner that was independent of fibrillin-1 synthesis. Fibrillin-1 deposition in the ECM was increased in transgenic mice overexpressing Adamtsl6-beta in cartilage. Tsutsui et al. (2010) concluded that ADAMTSL6 promotes assembly of fibrillin-1 microfibrils. Marfan syndrome (MFS; 154700) is a connective tissue disease caused by defective formation of fibrillin-1 microfibrils. MFS is associated with overactivation of TGF-beta (TGFB1; 190180) signaling due to increased release of active TGF-beta from disrupted fibrillin-1 microfibrils. Using a mouse model of MFS, Saito et al. (2011) showed that expression of Adamtsl6-beta rescued the formation of fibrillin-1 microfibrils in the periodontal ligament, one of several affected tissues in MFS. Adamtsl6 expression also attenuated overactivation of TGF-beta signaling in MFS mice. Using various in vitro, in vivo, and culture models, Saito et al. (2011) confirmed that Adamtsl6 is required for assembly of fibrillin-1 microfibrils.
Molecular genetics
Using exome sequencing in 35 French families with familial thoracic aortic aneurysms and a set of next-generation sequencing capture genes in 1114 unrelated patients with thoracic aneurysms and dissection, Elbitar et al. (2021) identified 5 families with a pathological heterozygous variant in the THSD4 gene (614476.0001-614476.0005). The mutations included two 1 bp deletions, one duplication and two nonsense mutations. In the 4 families with a positive family history, the mutation split with the disease. Functional studies showed that the variants resulted in haploinsufficiency, or an abnormal arrangement of fibrillin-1 microfibrils.
animal model
Elbitar et al. (2021) created a Thsd4 +/- mouse model and showed that heterozygous mice exhibited progressive dilatation of the thoracic aorta. Histological analysis showed normal elastic fiber formation from 0 to 5 months of age; However, patchy accumulation of Alcian blue positive areas in the aorta was observed at 6 and 9 months, suggesting the presence of proteoglycans.
ALLELIC VARIANTS 5 selected examples):
.0001 FAMILY THORACIC AORTIC ANORYSM 12
THSD4, LEU247TER
ClinVar: RCV002210954
Using exome sequencing, Elbitar et al. (2021) identified a 1 bp deletion (c.740del, NM_024817.2) in exon 4 of the THSD4 gene, resulting in a leu247 to ter (L247X) substitution in a mother and son (family 1, TAA- 1889) resulted in familial thoracic aortic aneurysm-12 (AAT12; 619825). Subject had a type A aortic dissection at age 43 and his mother had her ascending aorta replaced for a dissection at age 75. Other findings observed in the subject included a slight pectus excavatum, dolicostomelia, and a high arch of the palate.
.0002 FAMILY THORACIC AORTIC ANORYSM 12
THSD4, 1-BP DEL, 1402G
ClinVar: RCV002210955
In a family (Family 2, TAA-1839) with familial thoracic aortic aneurysm-12 (AAT12; 619825), Elbitar et al. (2021) identified a 1 bp deletion of a guanine in a 3-guanine repeat (c.1402delG, NM_024817.2) in exon 8 of the THSD4 gene, resulting in image shift and premature termination (Ala468GlnfsTer45). The female subject and her daughter had dilatation of the ascending aorta with diameters of 42 mm at the aortic root and 47 mm at the ascending aorta in the mother (age 48 years) and 28 mm at the aortic root and 32 mm at the ascending aorta. Aorta for daughter (age 16 years). Subject's sister had an aortic root diameter of 33 mm with 36 mm in the ascending aorta (age 46 years). The father (80 years old) who was a carrier of the variant was not known to be affected and was unavailable for study. The subject was also found to have dolicostomelia, hypertelorism, and arthritis.
.0003 FAMILY THORACIC AORTIC ANORYSM 12
THSD4, 9-BP DUP, NT137
ClinVar: RCV002210956
In a family (Family 3, TAA-1850) with familial thoracic aortic aneurysm-12 (AAT12; 619825), Elbitar et al. (2021) identified a 9 bp in-frame duplication in the THSD4 gene (c.137_145dup, NM_024817.2) that would likely result in a 3 amino acid residue duplication (Asp46_Gly48dup). The subject had an enlarged aortic root (48 mm) after a myocardial infarction at the age of 39 years. His brother also carried the duplication and underwent surgery for an aortic dissection at the age of 42, noting a dilatation of the ascending aorta prior to the dissection. The subject's father also carried the duplication and underwent aortic dilatation surgery of the ascending and abdominal aorta at age 68. No other clinical manifestations of connective tissue disorders were observed in the family.
.0004 FAMILY THORACIC AORTIC ANORYSM 12
THSD4, TYR321ASN
ClinVar: RCV002210957
In a patient (family 4; TAA-1817) with familial thoracic aortic aneurysm-12 (AAT12; 619825), Elbitar et al. (2021) identified a c.961T-A transversion (c.961T-A, NM_024817.2) in exon 5 of the THSD4 gene, resulting in a tyr321 to asn (Y321N) substitution. The subject required Bentall surgery for aortic regurgitation at the age of 61. The aortic root size was 44 mm (Z = 3.9 SD). The patient also had a spontaneous pneumothorax. His daughter was also a carrier of the variant and had an aortic root diameter of 30 mm and an ascending aortic diameter of 29 mm. This variant has not been reported in population databases.
.0005 FAMILY THORACIC AORTIC ANORYSM 12
THSD4, ARG781TRP ({dbSNP rs767807136})
ClinVar: RCV002204561
In a patient (family 5; TAA-1819) with familial thoracic aortic aneurysm-12 (AAT12; 619825), Elbitar et al. (2021) identified a transition c.2341C-T (c.2341C-T, NM_024817.2) in exon 13 of the THSD4 gene that resulted in a substitution of arg781 to trp (R781W). The subject underwent elective surgery at the age of 57 for an aortic root diameter of 50 mm. The subject also had Raynaud's syndrome and a bicuspid aortic valve. No other family members were affected. The variant had a frequency of 0.000035 among non-Finnish Europeans in the gnomAD database.
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Most (67.7%) are autosomal dominant disorders.
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