Anne W. Higgins

MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus

Cardiac left ventricular outflow tract (LVOT) defects represent a common but heterogeneous subset of congenital heart disease for which gene identification has been difficult. We describe a 46,XY,t(1;5)(p36.11;q31.2)dn translocation carrier with pervasive developmental delay who also exhibited LVOT defects, including bicuspid aortic valve (BAV), coarctation of the aorta (CoA) and patent ductus arteriosus (PDA). The 1p breakpoint disrupts the 5′ UTR of AHDC1, which encodes AT-hook DNA-binding motif containing-1 protein, and AHDC1-truncating mutations have recently been described in a syndrome that includes developmental delay, but not congenital heart disease [Xia, F., Bainbridge, M.N., Tan, T.Y., Wangler, M.F., Scheuerle, A.E., Zackai, E.H., Harr, M.H., Sutton, V.R., Nalam, R.L., Zhu, W. et al. (2014) De Novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am. J. Hum. Genet., 94, 784–789]. On the other hand, the 5q translocation breakpoint disrupts the 3′ UTR of MATR3, which encodes the nuclear matrix protein Matrin 3, and mouse Matr3 is strongly expressed in neural crest, developing heart and great vessels, whereas Ahdc1 is not. To further establish MATR3 3′ UTR disruption as the cause of the probands LVOT defects, we prepared a mouse Matr3Gt-ex13 gene trap allele that disrupted the 3′ portion of the gene. Matr3Gt-ex13 homozygotes are early embryo lethal, but Matr3Gt-ex13 heterozygotes exhibit incompletely penetrant BAV, CoA and PDA phenotypes similar to those in the human proband, as well as ventricular septal defect (VSD) and double-outlet right ventricle (DORV). Both the human MATR3 translocation breakpoint and the mouse Matr3Gt-ex13 gene trap insertion disturb the polyadenylation of MATR3 transcripts and alter Matrin 3 protein expression, quantitatively or qualitatively. Thus, subtle perturbations in Matrin 3 expression appear to cause similar LVOT defects in human and mouse.

Candidate loci for zimmermann-laband syndrome at 3p14.3

A male with 46,XY,t(3;17)(p14.3;q24.3) presented with gingival hyperplasia, hypertrichosis, unusually large ears and marked hypertrophy of the nose, characteristic of the Zimmermann–Laband syndrome (ZLS). Other features include large facial bones and mandibles, large protruding upper lip, enlarged fingers and toes, strabismus, and enlarged phallus. Knowledge of a 46,XX,t(3;8)(p21.2;q24.3) reported previously in a mother and daughter with ZLS suggests that the 3p14.3‐p21.2 region may contain a gene responsible for ZLS. We have reassessed the chromosome 3 breakpoint region of the t(3;8) and revised its breakpoint location to 3p14.3, based upon an updated human genome sequence assembly. Using fluorescence in situ hybridization (FISH) with BAC clones, we have also identified a breakpoint spanning clone at 3p14.3 in our t(3;17) patient, thereby narrowing the breakpoint to a region of approximately 200 kb. These data suggest that the gene responsible for ZLS is located in 3p14.3 and implicates four likely candidate genes in this region: CACNA2D3, encoding a voltage‐dependent calcium channel, LRTM1, a gene of unknown function embedded within CACNA2D3, WNT5A, encoding a secreted signaling protein of the WNT family, and ERC2, which codes for a synapse protein.

Extensive molecular genetic analysis of the 3p14.3 region in patients with Zimmermann–Laband syndrome†‡§

Zimmermann–Laband syndrome (ZLS) is a rare autosomal dominant inherited disorder characterized by a coarse facial appearance, gingival fibromatosis, and absence or hypoplasia of the terminal phalanges and nails of hands and feet. Additional, more variable features include hyperextensibility of joints, hepatosplenomegaly, mild hirsutism, and mental retardation. Mapping of the translocation breakpoints of t(3;8) and t(3;17) found in patients with the typical clinical features of ZLS defined a common breakpoint region of ∼280 kb located in 3p14.3, which includes the genes CACNA2D3 and WNT5A. Breakpoint cloning revealed that both translocations most likely occurred by non‐homologous (illegitimate) recombination. Mutation analysis of nine genes located in 3p21.1‐p14.3, including CACNA2D3, which is directly disrupted by one breakpoint of the t(3;17), identified no pathogenic mutation in eight sporadic patients with ZLS. Southern hybridization analysis and multiplex ligation‐dependent probe amplification (MLPA) did not detect submicroscopic deletion or duplication in either CACNA2D3 or WNT5A in ZLS‐affected individuals. Mutation analysis of nine conserved nongenic sequence elements (CNEs) in 3p21.1‐p14.3, which were identified by interspecies comparison and may represent putative regulatory elements for spatiotemporally correct expression of nearby genes, did not show any sequence alteration associated with ZLS. Taken together, the lack of a specific coding‐sequence lesion in the common region, defined by two translocation breakpoints, in sporadic patients with ZLS and an apparently normal karyotype suggests that either some other type of genetic defect in this vicinity or an alteration elsewhere in the genome could be responsible for ZLS.