RESUMEN
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.
Asunto(s)
Deformidades Congénitas de las Extremidades/genética , Microftalmía/genética , Osteonectina/genética , Animales , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 14/genética , Codón sin Sentido/genética , Extremidades/crecimiento & desarrollo , Ojo/crecimiento & desarrollo , Genes Recesivos , Sitios Genéticos , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Datos de Secuencia Molecular , Nervio Óptico/anomalías , Empalme del ARN/genética , Síndrome de Waardenburg/genéticaRESUMEN
Ophthalmo-acromelic syndrome (OAS, OMIM %206920) is a rare autosomal recessive disease, presenting with clinical anophthalmia and limb anomalies. We recruited three OAS families including a Japanese family with two affected patients and two consanguineous Lebanese families each having an affected. Homozygosity mapping was performed using the 50K SNP chip and additional informative markers. A locus for OAS was mapped to the 422-kb region at 10q11.23, based on the results from the two consanguineous families as well as the consistent data from the Japanese non-consanguineous family. The 422-kb region only contained one gene, MPP7. Although we could not detect any pathological mutations in OAS families analyzed, MPP7 could remain a candidate as aberrant changes might exist beyond our mutation detection methods. Further families are needed to confirm this candidate locus.
Asunto(s)
Anoftalmos/genética , Mapeo Cromosómico , Cromosomas Humanos Par 10 , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Femenino , Genes Recesivos , Marcadores Genéticos , Haplotipos , Homocigoto , Humanos , Deformidades Congénitas de las Extremidades/genética , Masculino , Proteínas de la Membrana/genética , Linaje , Polimorfismo de Nucleótido Simple , Radiografía , Hermanos , SíndromeRESUMEN
We describe four individuals (two females and two males) with Kabuki syndrome and recurrent dislocation of the patella. The age of diagnosis of patellar dislocation ranged from 11 to 23 years. One individual underwent excision of the free fragment and transfer of the tibial tuberosity with good outcome. Two required patellar brace for instability. Characteristics of individuals with the syndrome at a high risk of patellar dislocation include female, adolescence or young adulthood, joint laxity, and obesity.
Asunto(s)
Anomalías Múltiples/patología , Huesos/anomalías , Discapacidades del Desarrollo/patología , Luxaciones Articulares/patología , Rótula/lesiones , Adolescente , Adulto , Niño , Cara/anomalías , Femenino , Humanos , Discapacidad Intelectual/patología , Masculino , Anomalías Cutáneas , SíndromeRESUMEN
Sanfilippo type B syndrome (mucopolysaccharidosis type IIIB; MPS IIIB) is an autosomal recessive lysosomal storage disorder that is caused by defective alpha- N-acetylglucosaminidase (NAGLU). We performed NAGLU gene analysis in five patients with MPS IIIB whose respective parents from the Okinawa islands in Japan were not apparently consanguineous. We found a missense mutation (R565P) in all five patients (all homozygotes). We screened this mutation in 200 healthy subjects and found one heterozygote (none of the subjects were related to the patients). These results suggest that there may be a founder effect that results in the accumulation of R565P mutation in this area.