RESUMO
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.
Assuntos
Deformidades Congênitas dos Membros/genética , Microftalmia/genética , Osteonectina/genética , Animais , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 14/genética , Códon sem Sentido/genética , Extremidades/crescimento & desenvolvimento , Olho/crescimento & desenvolvimento , Genes Recessivos , Loci Gênicos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Dados de Sequência Molecular , Nervo Óptico/anormalidades , Splicing de RNA/genética , Síndrome de Waardenburg/genéticaRESUMO
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.
Assuntos
Anoftalmia/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 10 , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Genes Recessivos , Marcadores Genéticos , Haplótipos , Homozigoto , Humanos , Deformidades Congênitas dos Membros/genética , Masculino , Proteínas de Membrana/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Radiografia , Irmãos , SíndromeRESUMO
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.
Assuntos
Acetilglucosaminidase/genética , Mucopolissacaridose III/epidemiologia , Mucopolissacaridose III/genética , Mutação de Sentido Incorreto/genética , Adulto , Criança , Análise Mutacional de DNA , Primers do DNA , Testes Genéticos , Humanos , Japão/epidemiologia , Análise de Sequência de DNARESUMO
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.
