[email protected] (受疫情影响,东南亚目前只开放曼谷诊所)
全周 (9AM - 5PM)

我们和你在一起

Extra info thumb
  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
  • [email protected]
HETEROTAXY, VISCERAL, 8, AUTOSOMAL; HTX8

HETEROTAXY, VISCERAL, 8, AUTOSOMAL; HTX8

Autosomal visceral heterotaxy-8 is an autosomal recessive developmental disorder characterized by visceral situs inversus associated with complex congenital hear...

Autosomal visceral heterotaxy-8 is an autosomal recessive developmental disorder characterized by visceral situs inversus associated with complex congenital heart malformations caused by defects in the normal left-right asymmetric positioning of internal organs (summary by Vetrini et al., 2016).

For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955).

▼ Clinical Features
Vetrini et al. (2016) reported 2 male infants, born of unrelated parents of northern European descent, with heterotaxy and complex congenital heart disease resulting in death shortly after birth and at age 3 weeks. In 1 infant, the abnormalities were apparent on prenatal ultrasound at 21 weeks' gestation. The features were slightly different between the 2 sibs, but included atrial situs solitus, atrial situs ambiguus, unbalanced atrioventricular septal defect, left ventricular hypoplasia, double-outlet right ventricle with malposition of the great arteries, pulmonary atresia, right-sided stomach, left-sided liver, and right-sided spleen. Vetrini et al. (2016) also reported a 46-year-old woman, born of consanguineous Iranian parents. She was diagnosed in the first weeks of life with situs inversus totalis and congenital heart disease including congenitally corrected transposition of the great arteries (ventricular inversion) with a small left ventricle, pulmonary atresia, and ventricular septal defect. She underwent placement of a left ventricle to pulmonary artery conduit and ventricular septal defect closure. She has paroxysmal atrial flutter and a dual-chamber pacemaker.

▼ Inheritance
The transmission pattern of HTX8 in the families reported by Vetrini et al. (2016) was consistent with autosomal recessive inheritance.

▼ Molecular Genetics
In 2 male infants with HTX8 who died in infancy, Vetrini et al. (2016) identified a homozygous splice site mutation in the PKD1L1 gene (609721.0001). A 46-year-old woman from an unrelated family with HTX8 carried a homozygous missense mutation (C1691S; 609721.0002). The mutations were found by exome sequencing and segregated with the disorder in both families. Functional studies of the variants were not performed, but Vetrini et al. (2016) noted that several animal models had shown that disruption of the Pkd1l1 gene results in lateralization defects (see ANIMAL MODEL).

▼ Animal Model
Field et al. (2011) identified an ENU-induced recessive mutation in mouse Pkd1l1 that caused left-right patterning defects. They named the mutation 'rikishi' (rks) because of the similarity in shape between homozygous mutant embryos and Sumo wrestlers. The rks mutation is an A-to-G transition in the Pkd1l1 gene, resulting in an asp441-to-gly (D441G) substitution in a highly conserved WDFGDGS motif in the second PKD domain of the Pkd1l1 protein. Homology-based molecular modeling predicted that the mutation disrupts the structure of the second PKD domain. Pkd1l1 rks mutants exhibited gross left-right patterning abnormalities that phenocopied those found in mouse embryos homozygous for a glu442-to-gly (E442G) mutation in Pkd2. Both Pkd1l1 rks and Pkd2 E442G mutations resulted in embryonic lethality prior to 15.5 dpc, with high incidence of right pulmonary isomerism, randomization of stomach and cardiac asymmetry, outflow tract defects, and absence of asymmetric gene expression at the node and in the lateral plate. Both Pkd1l1 rks and Pkd2 E442G mutants had normal node size, length, and morphology and normal cilia number and motility.

Grimes et al. (2016) found that functional knockout of Pkd1l1 expression in mice via a targeted mutation (tm1) resulted in a phenotype distinct from that of Pkd1l1 rks/rks mice. Homozygosity for the rks mutation was embryonic lethal, but a proportion of Pkd1l1 tm1/tm1 mice survived to adulthood. Both mutations resulted in randomized laterality of heart and stomach, but Pkd1l1 rks/rks embryos exhibited right-lung isomerism, whereas the majority of Pkd1l1 tm1/tm1 embryos showed left-lung isomerism. Pkd1l1 rks/rks mice lacked Nodal cascade gene expression in lateral plate mesoderm, whereas Pkd1l1 tm1/tm1 mice showed strong bilateral Nodal cascade gene expression. Neither mutation altered ciliary architecture, function, or rotational movement. Grimes et al. (2016) hypothesized that PKD1L1 represses PKD2 in the node and that nodal flow relieves this repression on the left side only, activating PKD2 and initiating a signaling cascade that results in left-sided NODAL activity.

Tags: 7p12.3

相关文章

HETEROTAXY, VISCERAL, 8, AUTOSOMAL; HTX8
SEPTIN 13; SEPT13

HGNC Approved Gene Symbol: SE...

HETEROTAXY, VISCERAL, 8, AUTOSOMAL; HTX8
胰岛素样生长因子结合蛋白 3

胰岛素样生长因子 (IGF)、它们的受体和它们的结合蛋白在...

HETEROTAXY, VISCERAL, 8, AUTOSOMAL; HTX8
胰岛素样生长因子结合蛋白 1

与胰岛素不同,IGF I ( 147440 ) 和 IGF...

HETEROTAXY, VISCERAL, 8, AUTOSOMAL; HTX8
尿苷磷酸酶1

在存在正磷酸盐的情况下,已知的两种嘧啶核苷磷酸化酶分别为尿...

遇到问题了吗?