Andréa L. Sertié

Clinical spectrum of fibroblast growth factor receptor mutations.

During the last few years, it has been demonstrated that some syndromic craniosynostosis and short‐limb dwarfism syndromes, a heterogeneous group comprising of 11 distinct clinical entities, are caused by mutations in one of three fibroblast growth factor receptor genes (FGFR1, FGFR2, and FGFR3). The present review list all mutations described to date in these three genes and the phenotypes associated with them. In addition, the tentative phenotype‐genotype correlation is discussed, including the most suggested causative mechanisms for these conditions. Hum Mutat 14:115–125, 1999.

Genetics of Craniosynostosis: Genes, Syndromes, Mutations and Genotype-Phenotype Correlations

Craniosynostosis is a very heterogeneous group of disorders, in the etiology of which genetics play an important role. Chromosomal alterations are important causative mechanisms of the syndromic forms of craniosynostosis accounting for at least 10% of the cases. Mutations in 7 genes are unequivocally associated with mendelian forms of syndromic craniosynostosis: FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2 and RAB23. Mutations in 4 other genes, FBN1, POR, TGFBR1 and TGFBR2, are also associated with craniosynostosis, but not causing the major clinical feature of the phenotype or with an apparently low penetrance. The identification of these genes represented a great advance in the dissection of the genetics of craniosynostosis in the last 15 years, and today they explain the etiology of about 30% of the syndromic cases. The paucity in the identification of genes associated with this defect has partly been due to the rarity of familial cases. In contrast, very little is known about the molecular and cellular factors leading to nonsyndromic forms of craniosynostosis. Revealing the molecular pathology of craniosynostosis is also of great value for diagnosis, prognosis and genetic counseling. This chapter will review (1) the chromosomal regions associated with syndromic forms of the malformation, (2) the genes in which a large number of mutations have been reported by independent studies (FGFR1, FGFR2, FGFR3, TWIST1 and EFNB1) and (3) the molecular mechanisms and genotype-phenotype correlations of such mutations.

The Seventh Form of Autosomal Recessive Limb-Girdle Muscular Dystrophy Is Mapped to 17q11-12

The group of autosomal recessive (AR) muscular dystrophies includes, among others, two main clinical entities, the limb-girdle muscular dystrophies (LGMDs) and the distal muscular dystrophies. The former are characterized mainly by muscle wasting of the upper and lower limbs, with a wide range of clinical severity. This clinical heterogeneity has been demonstrated at the molecular level, since the genes for six AR forms have been cloned and/or have been mapped to 15q15.1 (LGMD2A), 2p12-16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D),4q12 (LGMD2E), and 5q33-34 (LGMD2F). The AR distal muscular dystrophies originally included two subgroups, Miyoshi myopathy, characterized mainly by extremely elevated serum creatine kinase (CK) activity and by a dystrophic muscle pattern, and Nonaka myopathy, which is distinct from the others because of the normal to slightly elevated serum CK levels and a myopathic muscle pattern with rimmed vacuoles. With regard to our unclassified AR LGMD families, analysis of the affected sibs from one of them (family LG61) revealed some clinical and laboratory findings (early involvement of the distal muscles, mildly elevated serum CK levels, and rimmed vacuoles in muscle biopsies) that usually are not observed in the analysis of patients with LGMD2A-LGMD2F. In the present investigation, through a genomewide search in family LG61, we demonstrated linkage of the allele causing this form of muscular dystrophy to a 3-cM region on 17q11-12. We suggest that this form, which, interestingly, clinically resembles AR Kugelberg-Welander disease, should be classified as LGMD2G. In addition, our results indicate the existence of still another locus causing severe LGMD.

Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter

We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan-Herndon-Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction. The c.1834delC segregates with the disease in this family and it was not present in 100 control chromosomes, further confirming its pathogenicity. This mutation causes a frameshift and the inclusion of 64 additional amino acids in the C-terminal region of the protein. Pathogenic mutations in the MCT8 gene, which encodes a thyroid hormone transporter, results in elevated serum triiodothyronine (T3) levels, which were confirmed in four affected males of this family, while normal levels were found among obligate carriers. Through in vitro functional assays, we showed that this mutation decreases cellular T3 uptake and intracellular T3 metabolism. Therefore, the severe neurological defects present in the patients are due not only to deficiency of intracellular T3, but also to altered metabolism of T3 in central neurones. In addition, the severe muscle hypoplasia observed in most AHDS patients may be a consequence of high serum T3 levels.

Description of a new mutation and characterization of FGFR1, FGFR2, and FGFR3 mutations among Brazilian patients with syndromic craniosynostoses

Dominant mutations in three fibroblast growth factor receptor genes (FGFRs1-3) cause Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. In the present study, 50 Brazilian patients with these four syndromes (27 Apert, 17 Crouzon, 5 Pfeiffer, and 1 Jackson-Weiss patients) were screened for mutations in the FGFR1-3 genes. Except for one, all the Apert patients had either S252W (n = 16) or P253R (n = 10) mutations. The remaining Apert case is atypical with a mutation altering the splice site of FGFR2 exon IIIc. The Pfeiffer patients had mutations in one of the FGFR genes: three in FGFR2, one in FGFR1, and one in FGFR3. In contrast, only 8 of the 17 Crouzon patients studied had a mutation in either FGFR2 (n = 7) or FGFR3 locus (n = 1). Mutations in the FGFR2 locus account for most (93%) of our syndromic craniosynostotic cases, whereas 5% had mutations in the FGFR3 locus and only 2% had mutations in the FGFR1 gene. Except for one, all the other mutations were reported previously in craniosynostotic patients from other populations. Interestingly, the mutation C278F, previously described in Crouzon and Pfeiffer cases, was here identified in a familial case with Jackson-Weiss. Also, unexpectedly, a common mutation altering the splice site of the FGFR2 exon IIIc was found in one Apert and two Pfeiffer patients. In addition, we identified a new mutation (A337P) in the FGFR2 exon IIIc associated with Crouzon phenotype.

New SMS mutation leads to a striking reduction in spermine synthase protein function and a severe form of Snyder–Robinson X-linked recessive mental retardation syndrome

We report the identification of a novel mutation at a highly conserved residue within the N-terminal region of spermine synthase (SMS) in a second family with Snyder–Robinson X-linked mental retardation syndrome (OMIM 309583). This missense mutation, p.G56S, greatly reduces SMS activity and leads to severe epilepsy and cognitive impairment. Our findings contribute to a better delineation and expansion of the clinical spectrum of Snyder–Robinson syndrome, support the important role of the N-terminus in the function of the SMS protein, and provide further evidence for the importance of SMS activity in the development of intellectual processing and other aspects of human development.

Mutations in collagen 18A1 (COL18A1) and their relevance to the human phenotype

Collagen XVIII, a proteoglycan, is a component of basement membranes (BMs). There are three distinct isoforms that differ only by their N-terminal, but with a specific pattern of tissue and developmental expression. Cleavage of its C-terminal produces endostatin, an inhibitor of angiogenesis. In its N-terminal, there is a frizzled motif which seems to be involved in Wnt signaling. Mutations in this gene cause Knobloch syndrome KS), an autosomal recessive disorder characterized by vitreoretinal and macular degeneration and occipital encephalocele. This review discusses the effect of both rare and polymorphic alleles in the human phenotype, showing that deficiency of one of the collagen XVIII isoforms is sufficient to cause KS and that null alleles causing deficiency of all collagen XVIII isoforms are associated with a more severe ocular defect. This review besides illustrating the functional importance of collagen XVIII in eye development and its structure maintenance throughout life, it also shows its role in other tissues and organs, such as nervous system and kidney.

Linkage Analysis in a Large Brazilian Family with van der Woude Syndrome Suggests the Existence of a Susceptibility Locus for Cleft Palate at 17p11.2-11.1

van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk <40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS. Our results suggest that a gene at 17p11.2-11.1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes. If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene. It will also have important implications for genetic counseling, particularly for more accurately predicting recurrence risks of clefts among the offspring of patients with VWS.

Presence of the Apert canonical S252W FGFR2 mutation in a patient without severe syndactyly.

Apert syndrome, characterised by craniosynostosis, craniofacial anomalies, and symmetrical syndactyly of the digits (cutaneous and bony fusion), has been associated with two canonical mutations in the FGFR2 gene (S252W, P253R) in the great majority of cases. Since these two alterations have been observed exclusively among these patients, it has been suggested that the S252W and P253R changes may play an important role in the occurrence of syndactyly. In order to verify whether the mutations S252W and P253R could also cause a milder phenotype, without involvement of the limbs, we have screened 22 patients with clinical characteristics compatible with Crouzon or Pfeiffer syndrome for these two particular changes. Surprisingly, we identified a Pfeiffer-like patient with the mutation S252W, and therefore we have shown for the first time the occurrence of one of the canonical Apert mutations without severe abnormalities of the upper and lower extremities.

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuron-specific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.