Two novel homozygous RAB3GAP1 mutations cause Warburg micro syndrome.
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ABSTRACT:
SUBMITTER: Imagawa E
PROVIDER: S-EPMC4785564 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Two novel homozygous RAB3GAP1 mutations cause Warburg micro syndrome.
Imagawa Eri E Fukai Ryoko R Behnam Mahdiyeh M Goyal Manisha M Nouri Narges N Nakashima Mitsuko M Tsurusaki Yoshinori Y Saitsu Hirotomo H Salehi Mansour M Kapoor Seema S Tanaka Fumiaki F Miyake Noriko N Matsumoto Naomichi N
Human genome variation 20150917
Warburg micro syndrome is an autosomal recessive disease where patients present with optic, neurologic and genital symptoms. Until now, four disease genes for Warburg micro syndrome, RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20, have been identified. Here, we report two novel homozygous RAB3GAP1 mutations (c.22G>T, p.Glu8* and c.1353delA, p.Pro452Hisfs*5) in two consanguineous families by whole-exome sequencing. ...[more]
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Project description:This report details two novel RAB3GAP1 mutations causing Warburg Micro syndrome, a rare autosomal recessive disorder characterized by multiple organ abnormalities involving the ocular, nervous, and endocrine systems. Two Italian sisters were referred to our department for the assessment of congenital bilateral cataracts. They also presented with microphthalmia, postnatal microcephaly, severe developmental delay, and hypotony. Perinatal investigations were negative for any toxins or infectious diseases during pregnancy, including toxoplasmosis, rubella, cytomegalovirus, and herpes virus. Genetic tests were performed on samples from probands and their parents, targeting a total of 114 genes. After sequence analysis of RAB3GAP1, two heterozygous changes were identified in both sisters: C.519G>A, p.(Trp173Ter) and c.2486T>A, p.(Leu829Ter). The identified mutations have not previously been described in the literature, but they affect critical regions of the gene, suggesting a legitimate causal relationship between the genetic alterations and the clinical features of the patients.
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Project description:Warburg micro syndrome (WARBM) is a genetic heterogeneous disease characterized by microcephaly, intellectual disability, brain, ocular, and endocrine anomalies. WARBM1-4 can be caused by biallelic mutations of the RAB3GAP1 (RAB3 GTPase-activating protein 1), RAB3GAP2, RAB18 (RAS-associated protein RAB18), or TBC1D20 (TBC1 domain protein, member 20) gene, respectively. Here, we delineate the so far largest intragenic homozygous RAB3GAP1 microdeletion. Despite the size of the RAB3GAP1 gene deletion, the patient phenotype is mainly consistent with that of other WARBM1 patients, supporting strongly the theory that WARBM1 is caused by a loss of RAB3GAP1 function. We further highlight osteopenia as a feature of WARBM1.
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Project description:In this study, we detected a novel pathogenic variant and a previously reported variant in RAB3GAP1 by whole-exome sequencing (NM_001172435.2: c.1552C>T, p.Gln518*; c.1471C>T, p.Arg491*). The first patient is a 3-year-old girl who presented with bilateral congenital cataracts, developmental delay, abnormal craniofacial features, drug-resistant constipation, and corpus callosum hypoplasia. The proband of the second family is a 13-year-old boy who suffers from developmental delay, quadriplegia, intellectual disability, abnormal craniofacial features, and corpus callosum hypoplasia.
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Project description:Background and purposeWarburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disease characterized by ocular, neurologic, and endocrine anomalies. WARBM is a phenotypically and genetically heterogeneous syndrome caused by mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20. Here we present the clinical and genetic characterization of a consanguineous Tunisian family with a WARBM phenotype presenting two pathogenic variations, one of which is on RAB3GAP1.MethodsWe applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype.ResultsWe reveal a new variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) and another variation in ABCD1 (NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in ABCD1, our patients did not have any X-linked symptoms of adrenoleukodystrophy disorder that are usually caused by ABCD1 mutations, which prompted our interest in clinical monitoring.ConclusionsWES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.
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Project description:Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Previously, identification of mutations in RAB3GAP1 and RAB3GAP2 in both these syndromes implicated dysregulation of the RAB3 cycle (which controls calcium-mediated exocytosis of neurotransmitters and hormones) in disease pathogenesis. RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the hetrodimeric enzyme RAB3GAP (RAB3GTPase-activating protein), a key regulator of the RAB3 cycle. We performed autozygosity mapping in five consanguineous families without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18. A c.71T > A (p.Leu24Gln) founder mutation was identified in four Pakistani families, and a homozygous exon 2 deletion (predicted to result in a frameshift) was found in the fifth family. A single family whose members were compound heterozygotes for an anti-termination mutation of the stop codon c.619T > C (p.X207QextX20) and an inframe arginine deletion c.277_279 del (p.Arg93 del) were identified after direct gene sequencing and multiplex ligation-dependent probe amplification (MLPA) of a further 58 families. Nucleotide binding assays for RAB18(Leu24Gln) and RAB18(Arg93del) showed that these mutant proteins were functionally null in that they were unable to bind guanine. The clinical features of Warburg Micro syndrome patients with RAB3GAP1 or RAB3GAP2 mutations and RAB18 mutations are indistinguishable, although the role of RAB18 in trafficking is still emerging, and it has not been linked previously to the RAB3 pathway. Knockdown of rab18 in zebrafish suggests that it might have a conserved developmental role. Our findings imply that RAB18 has a critical role in human brain and eye development and neurodegeneration.
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Project description:RationaleWarburg Micro syndrome is a rare, autosomal recessive disorder characterized by multiple organ abnormalities involving the ocular, nervous, and genital systems. This case report describes a novel mutation in the RAB3GAP1 gene associated with Warburg Micro syndrome.Patient concernsA 6-month-old female infant with bilateral congenital cataracts and developmental delay was referred to our department for further assessment. She presented with facial dysmorphic features, including a prominent forehead, microphthalmia, wide nasal bridge, relatively narrow mouth, large anteverted ears, and micrognathia.DiagnosesThe patient was diagnosed with Warburg Micro syndrome based on clinical manifestations, as well as a novel homozygous mutation in RAB3GAP1: c.75-2A>C. Both parents were identified as heterozygotic carriers of this mutation.InterventionsBilateral cataract extraction and anterior vitrectomy were performed at age 6 months, followed by physical rehabilitation. Convex lenses were used to protect the eyes postoperatively until intraocular lens implantation.OutcomesAlthough the patient received physical rehabilitation, she suffered global developmental delay.LessonsThe c.75-2A>C mutation in RAB3GAP1 expands the spectrum of known mutations in this gene, and it may be associated with Warburg Micro syndrome. Genetic counselors may wish to take this finding into consideration, especially given the poor prognosis associated with the disease.
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Project description:BackgroundThe present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients.Case presentationA 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant-NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)-in the RAB3GAP1 gene was identified as the most likely disease-causing variant. RT-PCR/RT-qPCR showed that this variant can activate a cryptic site of splicing in intron 3, changing the splicing and gene expression processes. We also identified some novel manifestations in association with WARBM type 1 to touch upon abnormal philtrum, prominent antitragus, downturned corners of the mouth, malaligned teeth, scrotal hypoplasia, low anterior hairline, hypertrichosis of upper back, spastic diplegia to quadriplegia, and cerebral white matter signal changes.ConclusionsDue to the common phenotypes between WARBMs and Martsolf syndrome (MIM: 212720), we suggest using the "RABopathies" term that can in turn cover a broad range of manifestations. This study can per se increase the genotype-phenotype spectrum of WARBM type 1.
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