Luz María González-Huerta

Hereditary sensory and autonomic neuropathy II due to novel mutation in the HSN2 gene in Mexican families

Mutations in the WNK1/HSN2 (with-no-lysine(K)-1/ hereditary sensory neuropathy 2) gene cause autosomal recessive HSAN2 [1, 2]. HSAN2, an early onset ulceromutilating sensory neuropathy, is clinically characterized by impairment of pain, temperature, and touch sensation. Other characteristics are loss of tendon reflexes, finger ulcers, frequent amputations and virtual absence of myelinated fibers with decreased numbers of unmyelinated fibers in sural nerves [3]. The HSN2, located on 12p13.33, is a nervous systemspecific exon of WNK1 and is referred to as the WNK1/ HSN2 isoform. WNK1/HSN2 encodes a polypeptide of 434 amino acids with a high expression in dorsal root ganglia and sciatic nerves [1, 2]. Apart from HSN2 mutations, a compound heterozygous mutation in exon 6 of WNK1 and in HSN2 [2] and mutations in FAM134B (family with sequence similarity 134, member B) [4] have been identified in HSAN2 demonstrating locus heterogeneity. In the present study, we analyzed two Mexican families with HSAN2 and identified a novel mutation in the WNK1/ HSN2 gene. We evaluated four out of five patients with HSAN2 and 16 healthy members belonging to two families. Family pedigrees are described in Fig. 1 and clinical characteristics are shown in Table 1. Clinical pictures and CT are shown in Fig. 2. Both families came from Chiapas (southeast of Mexico) of distant communities (Ocosingo and San Cristobal de las Casas). Careful examination of heterozygous carriers showed no clinical manifestations. Genomic DNA was extracted from 20 family members and 150 normal controls using standard techniques [5]. The WNK1/HSN2 gene was amplified through PCR [1] and directly sequenced using an ABI Prism Genetic Analyzer (Applied Biosystems, Foster City, CA, USA.) under the supplier’s conditions. All procedures were repeated twice. All members were informed about the characteristics of the study and they agreed to participate. We identified a homozygous mutation in WNK1/HSN2 in affected members of the two HSAN2 families. This mutation is a deletion of eight nucleotides (c. 1219_1226 delTCTCAGCA, NM 213655) that causes a novel stop codon 26 nucleotides after the original stop codon (S407fsX442) (Fig. 1). This mutation was not found in 150 normal controls and healthy members of the family, so we discarded a possible polymorphism. Subjects I1, I2, and III9 from family B were heterozygous with no clinical manifestations. Several mutations in WNK1/HSN2 have been identified among several populations: in Canada E198fs207, S307fsX319, Q315X; in Italy P85fsX98, G. Pacheco-Cuellar L. M. Gonzalez-Huerta J. M. Valdes-Miranda S. A. Cuevas-Covarrubias (&) Servicio de Genetica, Hospital General de Mexico, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Dr. Balmis 148, Col. Doctores, C.P. 06726 Mexico City, DF, Mexico e-mail: sercuevas@yahoo.com; sergioa@servidor.unam.mx

Novel Mutation and White Matter Involvement in an Indian Child with Pycnodysostosis

Pycnodysostosis (OMIM # 265800) is an inherited lysosomal disorder due to affection of cathepsin K gene, localised to 1q21. Pycnodysostosis can present with both skeletal and extraskeletal features. The index patient presented with cardinal features of short stature, dental and digital anomalies with history of multiple fractures. He, in addition had an unreported finding of white matter hyperintensity suggesting dysmyelination on neuroimaging. Molecular analysis revealed a homozygous insertion of single nucleotide in exon 5 of the CTSK gene that produces the substitution of phenylalanine instead of leucine at position 160 of protein and a premature termination of protein synthesis due to insertion of a stop codon. This mutation (c.480_481insT), (p.L160fsX173) is a novel frameshift mutation. The index case extends the phenotypic spectrum and the list of previously reported mutations in the CTSK gene.

ADRB1 and ADBR2 gene polymorphisms and the ocular hypotensive response to topical betaxolol in healthy Mexican subjects.

Abstract Background: The β adrenergic receptors (ADRB) are expressed in the ciliary body and trabecular meshwork, structures involved in aqueous humor production and outflow, respectively. ADRB are members of the adrenergic family of G-protein-coupled receptors. Topic β blockers have a good local and systemic tolerance; they reduce the aqueous humor production and eye strain blocking the ADRB of the ciliary body and interfering with adenylate cyclase. However, the ocular hypotensive response is not the same in all patients and could be mediated by the polymorphisms of the ADRB genes. Materials and methods: Seventy-two healthy subjects were studied after treatment with topical betaxolol in both eyes. We analyzed ADRB1 and ADRB2 gene polymorphisms by PCR and automated DNA sequencing. Results: There was statistically significant difference between baseline intraocular pressure (IOP) and final IOP of both eyes (baseline IOP 16.2u2009±u20091.2 – follow-up IOP 13.6u2009±u20092.0 (mean difference–2.5u2009±u20091.3, pu2009<u20090.001). Gly389 had a higher baseline IOP than Arg389 (17.0u2009±u20091.2u2009mmHg versus 16.0u2009±u20091.2u2009mmHg; pu2009=u20090.02), and conversely Arg389 had a greater magnitude of response than Gly389 to betaxolol therapy (−2.9u2009±u20091.1u2009mmHg versus −0.7u2009±u20090.4u2009mmHg; pu2009<u20090.001). Gln27 had a higher response than Glu27 (−2.7u2009±u20091.3u2009mmHg versus −1.9u2009±u20091.0; pu2009=u20090.02). Conclusion: Arg389 polymorphism of the ADRB1 gene and Gln27 polymorphism of the ADRB2 gene were associated with the hypotensive response to topic betaxolol in healthy Mexican volunteers.

Complete monosomy mosaic of chromosome 21: Case report and review of literature

Complete monosomy mosaic of chromosome 21 is a rare disorder. The syndromic features are highly variable. This study describes a girl of Mexican origin with complete monosomy 21 in mosaicism with novel findings, including cortical atrophy, macrostomia, pectum excavatum and immune deficiencies. Parental karyotypes were normal. FISH analysis with probes from 21q22.1-q22.2 region and centromere of X DNA probe was performed on peripheral blood lymphocytes whereas 21q22.1-q22.2 and 21q, 4p, 4q subtelomeric DNA probes were tested in fibroblasts. We propose that the monosomy 21 mosaicism is the cause of the survival of children with more than 4 months of age.

Particular distribution of the GJB2/GJB6 gene mutations in Mexican population with hearing impairment

BACKGROUNDnHereditary sensorineural hearing loss (SNHL) is a genetically heterogeneous disorder worldwide. Mutations in the GJB2 gene are a frequent cause of hereditary SNHL. There is a prevalence of certain mutations in various populations which suggests that specific mutations may be influenced by ethnic background.nnnOBJECTIVEnTo analyze the prevalence of GJB2, GJB6 mutations in several geographic areas of Mexico in patients with hereditary SNHL.nnnMATERIALS AND METHODSnOne hundred and forty Mexican unrelated propositi with prelingual SNHL were included in the study. All patients had three previous generations born in Mexico and belonged to no specific ethnic group. Analyses of the GJB2 and GJB6 genes and mt.1555A<G were performed in all subjects.nnnRESULTSnTwenty-three homozygous mutations, 57 heterozygous mutations, 1 double heterozygous (GJB2/GJB6) and 59 wild-type genotypes in the GJB2 gene were observed. Three patients had the homozygous c.del35 mutation whereas 26 patients were heterozygous for this gene defect. Only one patient with the GJB6 gene deletion was present (it includes the double heterozygous GJB2/GJB6). The mt.1555A>G mutation was not detected.nnnCONCLUSIONnWe found a great variety of mutations depending on the analyzed region in patients with SNHL; 57.86% of patients had affection in one or two alleles in GJB2 or GJB6 genes whereas 42.14% were wild-type. In some cases, allele distribution depended on region. Molecular studies of more genes involved in hereditary non-syndromic SNHL are required to completely confirm the molecular basis of hearing loss in Mexican population.

Noonan syndrome: prenatal diagnosis in a woman carrying a PTPN11 gene mutation.

Objective.u2003To describe the case of a pregnant woman and her fetus with Noonan syndrome (NS) whom were diagnosed through ultrasonography 3D and molecular analysis of the PTPN11 gene. Study design.u2003Case report. Results.u2003We detected in a pregnant woman and her child the G<A transition at position 236 in exon 3 of the PTPN11 gene causative of NS. Antenatal diagnosis was possible through ultrasonography in the 24th week of gestation. Conclusions.u2003Ultrasonography 3D is useful in the antenatal diagnosis of major congenital anomalies. Molecular studies should also be included to confirm the specific diagnosis.

Atypical X-linked ichthyosis in a patient with a large deletion involving the steroid sulfatase (STS) gene.

A 70‐year‐old male presented with very large, thick, tightly adherent, dark‐brown scales on the front of his lower extremities. His face, neck, back, abdomen, upper extremities, flexural areas, palms and soles as well as hair and nails were not involved. Family history was negative for similar lesions. Otherwise, the patient had a normal development. Onset of symptoms occurred during childhood with scales on lower extremities with no more additional features. Treatment included emollients exclusively with partial and temporary remission of cutaneous lesions. Recently, the patient had not received topical or systemic medical treatment. Laboratory investigations were within normal limits.

Familial Blau syndrome without uveitis caused by a novel mutation in the nucleotide-binding oligomerization domain-containing protein 2 gene with good response to infliximab

The proband in this study was a 4‐year‐old Mexican girl with Blau syndrome. She and her affected family members had skin rash and arthritis but no uveitis. Exome sequencing and DNA direct sequencing from blood samples revealed a novel nucleotide‐binding oligomerization domain‐containing protein 2 gene mutation in the affected family members. This study is the first report of a Mexican family with Blau syndrome showing good infliximab treatment response. The novel mutation in the nucleotide‐binding oligomerization domain‐containing protein 2 gene (c.1808A>G) enriches the mutation spectrum in Blau syndrome. This family represents one of the few cases of autosomal Blau syndrome with no uveitis; because of phenotype variability, it is important to recognize Blau syndromes clinical spectrum and recommend genetic consultation.

Two novel compound heterozygous families with a trimutation in the GJB2 gene causing sensorineural hearing loss.

BACKGROUNDnSensorineural hearing loss (SNHL) is a genetically heterogeneous disease. GJB2 gene mutations seem to be the most frequent cause of hereditary hearing impairment in several populations. There is variability in the mutations in the GJB2 gene worldwide; this remarks the influence of ethnic background in SNHL.nnnOBJECTIVEnTo describe the presence of two trimutations in the GJB2 gene in two Mexican families with hereditary SNHL.nnnMATERIALS AND METHODSnTwo unrelated Mexican families with prelingual SNHL were included in the study. Analysis of the GJB2 gene through PCR and DNA direct sequencing analysis was performed in all members of the families and in 100 normal controls.nnnRESULTSnAffected member of the family 1 showed the trimutation p.S19R/p.R32S/p.E47*, whereas affected members of the family 2 showed the trimutation p.F31I/p.W44*/p.V84M. Parents of both families were heterozygous with normal audition.nnnCONCLUSIONnWe found a novel mutation in the GJB2 gene and two trimutations with SNHL not previously reported. This remarks the complexity in the pattern of mutations in the GJB2 gene in SNHL and enriches the spectrum of the type of molecular defects in the GJB2 gene.

Discordant retinoblastoma in monozygotic twins due to deletion of 13q14.

Purpose To report discordant retinoblastoma in monozygotic twins, confirmed by GeneScan. Methods One twin presented unilateral retinoblastoma that was treated with enucleation; the other twin had no retinoblastoma. To confirm monozygosity, DNA from leukocytes was analyzed through GeneScan with highly polymorphic markers; to exclude 13q14 deletion, FISH analysis was performed in leukocytes and oral cells of both twins and their parents and in retinal tissue of the affected twin with the cDNA LSI RB1 probe. Results GeneScan analysis confirmed monozygosity. 13q14 deletion was observed in homozygous state in retinal tissue and in heterozygous state in oral cells and leukocytes of the affected twin. The nonaffected twin and parents showed no deletion of 13q14. Conclusions These data show unexpected differences in monozygotic twins that could be explained by postzygotic events in embryonic development.