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Studies reveal that disruption of the podosome adaptor protein TKS4 causes the skeletal dysplasia, eye and cardiac abnormalities of the autosomal-recessive disorder Frank-Ter Haar syndrome (FTHS). An analysis identifies homozygous mutations of the SH3PXD2B gene which encodes the TKS4 protein as the cause of the disorder.

A genome-wide single-nucleotide polymorphism (SNP) haplotype analysis is conducted to determine the causes of the recessive cone-rod dystrophies, the inherited dystrophies of the retina. The mutations in the ancient conserved domain protein 4 gene (CNNM4) are shown to widely cause the dystrophy with amelogenesis imperfecta.

A study on Lebanese Muslim family who were affected with odonto-onycho-dermal dysplasia was conducted. Result show an ectodermal dysplasia caused by an altered WNT signaling pathway.

The identification of mutations in FGD4 encoding FGD4/FGD1-related F-actin binding protein (FRABIN) in two families with members affected with Charcot-Marie-Tooth type 4H (CMT4H) disorder is reported. The results have concluded that FRABIN is the sixth protein related to guanosine triphosphate binding proteins (GTPase) signaling but the first Rho GDP/GTP nucleotide exchange factor (GEF) to be identified in CMT disease.

A common interstitial microdeletion of 200 kb on chromosome 1q21.1 in investigated 30 patients with TAR syndrome is described which is detected by microarray-based comparative genomic hybridization. Analysis of the patients reveals that deletion occurred de novo in 25% of affected individuals and this microdeletion is the prerequisite for the phenotype.

Linkage studies are performed in families with Escobar syndrome and eight mutations are identified within the gamma-subunit gene (CHRNG) of the acetylcholine receptor (AChR). The results have shown that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis and as gamma expression is restricted to early development, patients have no myasthenic symptoms later in life.

Microphthalmia with limb anomalies (MLA) is a rare autosomal-recessive disorder, presenting with anophthalmia or microphthalmia and hand and/or foot malformation. We mapped the MLA locus to 14q24 and successfully identified three homozygous (one nonsense and two splice site) mutations in the SPARC (secreted protein acidic and rich in cysteine)-related modular calcium binding 1 (SMOC1) in three families. Smoc1 is expressed in the developing optic stalk, ventral optic cup, and limbs of mouse embryos. Smoc1 null mice recapitulated MLA phenotypes, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed. Soft tissue syndactyly, resulting from inhibited apoptosis, was related to disturbed expression of genes involved in BMP signaling in the interdigital mesenchyme. Our findings indicate that SMOC1/Smoc1 is essential for ocular and limb development in both humans and mice. [ABSTRACT FROM AUTHOR]

Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the g-subunit gene (CHRNG) of the AChR. Our functional studies show that g-subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two a, one b, and one d subunit are always present. By switching γ to ϵ subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the g subunit were thought to be lethal, as they are in γ-knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because g expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway. [ABSTRACT FROM AUTHOR]