Browsing by Author "Sousa, SB"
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- Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndromePublication . Sousa, SB; Jenkins, D; Chanudet, E; Tasseva, G; Ishida, M; Anderson, G; Docker, J; Ryten, M; Sá, J; Saraiva, JM; Barnicoat, A; Scott, R; Calder, A; Wattanasirichaigoon, D; Chrzanowska, K; Simandlová, M; Van Maldergem, L; Stanier, P; Beales, PL; Vance, JE; Moore, GELenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.
- Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literaturePublication . Sentchordi-Montané, L; Aza-Carmona, M; Benito-Sanz, S; Barreda-Bonis, AC; Sánchez-Garre, C; Prieto-Matos, P; Ruiz-Ocaña, P; Lechuga-Sancho, A; Carcavilla-Urquí, A; Mulero-Collantes, I; Martos-Moreno, GA; Del Pozo, A; Vallespín, E; Offiah, A; Parrón-Pajares, M; Dinis, I; Sousa, SB; Ros-Pérez, P; González-Casado, I; Heath, KEOBJECTIVE: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis. DESIGN AND METHODS: This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals. RESULTS: A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies. CONCLUSIONS: ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias.
- Intellectual disability, coarse face, relative macrocephaly, and cerebellar hypotrophy in two sistersPublication . Sousa, SB; Ramos, F; Garcia, P; Pais, RP; Paiva, C; Beales, PL; Moore, GE; Saraiva, JM; Hennekam, RCWe report on two Portuguese sisters with a very similar phenotype characterized by severe intellectual disability, absent speech, relative macrocephaly, coarse face, cerebellar hypotrophy, and severe ataxia. Additional common features include increased thickness of the cranial vault, delayed dental eruption, talipes equino-varus, clinodactyly, and camptodactyly of the fifth finger. The older sister has retinal dystrophy and the younger sister has short stature. Their parents are consanguineous. We suggest this condition constitutes a previously unreported autosomal recessive entity.
- Intellectual disability, unusual facial morphology and hand anomalies in sibsPublication . Sousa, SB; Venâncio, M; Chanudet, E; Palmer, R; Ramos, L; Beales, PL; Moore, GE; Saraiva, JM; Hennekam, RCHere we report on a Portuguese family with three sisters who shared moderate intellectual disability, unusual facial morphology (short palpebral fissures; broad nasal tip; thin upper and lower vermillion; broad and pointed chin) and hand anomalies in two of them (short left third and fifth right metacarpals in one case; marked syndactyly between the third and fourth fingers in another). One of the sisters had microcephaly and short stature, and the other two were obese. Obesity and somewhat similar facial features were also present in the otherwise healthy mother. Despite the overlap with several known syndromes (Albright osteodystrophy; Filippi syndrome; Rubinstein-Taybi syndrome; microdeletion 2q37), we suggest this condition is previously unreported, and most likely displays an autosomal recessive pattern of inheritance.
- Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndromePublication . Thomas, AC; Williams, H; Setó-Salvia, N; Bacchelli, C; Jenkins, D; O'Sullivan, M; Mengrelis, K; Ishida, M; Ocaka, L; Chanudet, E; James, C; Lescai, F; Anderson, G; Morrogh, D; Ryten, M; Duncan, AJ; Pai, YJ; Saraiva, JM; Ramos, F; Farren, B; Saunders, D; Vernay, B; Gissen, P; Straatmaan-Iwanowska, A; Baas, F; Wood, NW; Hersheson, J; Houlden, H; Hurst, J; Scott, R; Bitner-Glindzicz, M; Moore, GE; Sousa, SB; Stanier, PIntellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.