Martsolf Syndrome Research Articles

Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report

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.

Martsolf syndrome with novel mutation in the TBC1D20 gene in a family from Iran

Warburg Micro syndrome and Martsolf syndrome are phenotypically overlapping autosomal recessive conditions characterized by multiple organ abnormalities involving the ocular, nervous, and endocrine systems. Warburg Micro syndrome, the more severe of the two conditions, is caused by loss of function mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 genes, whereas Martsolf syndrome has been attributed to less damaging mutations in RAB3GAP1 and RAB3GAP2 genes. We report the clinical description and molecular characterization of a consanguineous Iranian family with two siblings, a male and a female, with dysmorphic features, bilateral congenital cataracts, optic nerve atrophy, congenital glaucoma, mild to moderate intellectual disability, seizures, hypogonadism, and mild osteoporosis. Spastic quadriplegia with contractures was observed in the male patient, while the female patient showed only mild hyperreflexia. Magnetic resonance imaging scans performed in the male patient showed a normal brain structure. Both siblings had neither microcephaly nor postnatal growth retardation. Whole exome sequencing identified a novel homozygous nonsense mutation [c.1060C>T; p.(Arg354Ter)] in the TBC1D20 gene in both siblings and confirmed the heterozygous carrier status of both parents. This report describes a novel mutation in the TBC1D20 gene in two Iranian patients with Martsolf syndrome, further extending the allelic heterogeneity and phenotypic spectrum of this rare condition. The genotype and phenotype of the patients are compared with those of Martsolf syndrome and Warburg Micro syndrome patients reported in the literature.

Early detection of bilateral cataracts in utero may represent a manifestation of severe congenital disease.

We observed bilateral cataracts on second trimester ultrasound, in two consecutive pregnancies, with no other structural defects detected. The parents were unrelated and had no family history for the disease. The first pregnancy was terminated in week 22. Copy number variation analysis revealed, in both the aborted fetus and the mother, a 495 kb duplication at 22q11.23 encompassing CRYBB3 and CRYBB2, and not present in variation databases. In the second pregnancy, lens hyperechogenicity was detected by ultrasound at week 13 and 4 days. The identical duplication at 22q11.23 was found in the fetus and considered as possibly pathogenic. At weeks 22 and 30, smaller orbit measurements were elucidated on ultrasound, raising concerns as to the underlying molecular genetic cause, necessitating further investigation. Whole-exome sequencing, using DNA of the first fetus, was performed shortly after the birth of a male child, and two truncating RAB3GAP1 mutations were detected: c.538G>T; p. (Glu180*) and c.943C>T; p. (Arg315*). Neither mutation has been previously reported to be disease-causing; however, evaluation in the context of previously published literature indicated their deleterious nature, implying a clinical diagnosis of Warburg micro syndrome or Martsolf syndrome. Sanger sequencing confirmed segregation of the two mutations within the family, consistent with autosomal recessive inheritance. The child born from the second pregnancy showed features typical of Warburg micro syndrome, with the exception of microcephaly, at age 31 months. © 2016 Wiley Periodicals, Inc.

Mutation Spectrum inRAB3GAP1,RAB3GAP2, andRAB18and Genotype-Phenotype Correlations in Warburg Micro Syndrome and Martsolf Syndrome

Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.

RAB3GAP1, RAB3GAP2 and RAB18: disease genes in Micro and Martsolf syndromes

Micro syndrome (OMIM 60018) and Martsolf syndrome (OMIM 21270) are related rare autosomal recessive disorders characterized by ocular and neurological abnormalities and hypothalamic hypogonadism. Micro syndrome has been associated with causative mutations in three disease genes: RAB3GAP1, RAB3GAP2 and RAB18. Martsolf syndrome has been associated with a mutation in RAB3GAP2. The present review summarizes the current literature on these genes and the proteins they encode.

Loss-of-Function Mutations in RAB18 Cause Warburg Micro Syndrome

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.

PP-202. Microcephaly, bilateral cataract, and hypogonadism in a newborn: Martsolf syndrome

PP-202. Microcephaly, bilateral cataract, and hypogonadism in a newborn: Martsolf syndrome

A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome

Warburg Micro syndrome and Martsolf syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, postnatal microcephaly, and developmental delay. The neurodevelopmental and ophthalmological phenotype is more severe in Warburg Micro syndrome in which cerebral malformations and severe motor and mental retardation are common. While biallelic loss-of-function mutations in RAB3GAP1 are present in the majority of patients with Warburg Micro syndrome; a hypomorphic homozygous splicing mutation of RAB3GAP2 has been reported in a single family with Martsolf syndrome. Here, we report a novel homozygous RAB3GAP2 small in-frame deletion, c.499_507delTTCTACACT (p.Phe167_Thr169del) that causes Warburg Micro syndrome in a girl from a consanguineous Turkish family presenting with congenital cataracts, microphthalmia, absent visually evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay. No RAB3GAP2 mutations were detected in ten additional unrelated patients with RAB3GAP1-negative Warburg Micro syndrome, consistent with further genetic heterogeneity. In conclusion, we provide evidence that RAB3GAP2 mutations are not specific to Martsolf syndrome. Rather, our findings suggest that loss-of-function mutations of RAB3GAP1 as well as functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome while hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype. Thus, a phenotypic severity gradient may exist in the RAB3GAP-associated disease continuum (the "Warburg-Martsolf syndrome") which is presumably determined by the mutant gene and the nature of the mutation.

Rab proteins and Rab-associated proteins: major actors in the mechanism of protein-trafficking disorders

Ras-associated binding (Rab) proteins and Rab-associated proteins are key regulators of vesicle transport, which is essential for the delivery of proteins to specific intracellular locations. More than 60 human Rab proteins have been identified, and their function has been shown to depend on their interaction with different Rab-associated proteins regulating Rab activation, post-translational modification and intracellular localization. The number of known inherited disorders of vesicle trafficking due to Rab cycle defects has increased substantially during the past decade. This review describes the important role played by Rab proteins in a number of rare monogenic diseases as well as common multifactorial human ones. Although the clinical phenotype in these monogenic inherited diseases is highly variable and dependent on the type of tissue in which the defective Rab or its associated protein is expressed, frequent features are hypopigmentation (Griscelli syndrome), eye defects (Choroideremia, Warburg Micro syndrome and Martsolf syndrome), disturbed immune function (Griscelli syndrome and Charcot–Marie–Tooth disease) and neurological dysfunction (X-linked non-specific mental retardation, Charcot–Marie–Tooth disease, Warburg Micro syndrome and Martsolf syndrome). There is also evidence that alterations in Rab function play an important role in the progression of multifactorial human diseases, such as infectious diseases and type 2 diabetes. Rab proteins must not only be bound to GTP, but they need also to be ‘prenylated’—i.e. bound to the cell membranes by isoprenes, which are intermediaries in the synthesis of cholesterol (e.g. geranyl geranyl or farnesyl compounds). This means that isoprenylation can be influenced by drugs such as statins, which inhibit isoprenylation, or biphosphonates, which inhibit that farnesyl pyrophosphate synthase necessary for Rab GTPase activity. Conclusion: Although protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents.

Martsolf syndrome in Japanese siblings

We describe a Japanese brother and sister with Martsolf syndrome. They had short stature, severe mental retardation, cataract, hypogonadism, craniofacial dysmorphism, and bone and joint symptoms including scoliosis, lax finger joints, and talipes valgus. Previously undescribed findings included proximal femoral epiphyseal dysplasia reminiscent of Legg-Calve-Perthes disease in both patients, and Klippel-Feil malformation and osteopathia striata in one patient. Brain MRI showed mild frontal and temporal lobe atrophy, and mild ventricular enlargement. Severe GH deficiency was demonstrated after insulin tolerance and glucagon/propranolol tolerance tests. No responses to serum LH and FSH after a gonadotropin-releasing hormone (GnRH) test suggested secondary hypogonadism, that is, hypogonadotropic hypogonadism, due to hypothalamus-pituitary axis insufficiency in both patients.

Mutation in Rab3 GTPase-Activating Protein (RAB3GAP) Noncatalytic Subunit in a Kindred with Martsolf Syndrome

We identified a homozygous missense mutation in the noncatalytic subunit (RAB3GAP2) of RAB3GAP that results in abnormal splicing in a family with congenital cataracts, hypogonadism, and mild mental retardation (Martsolf syndrome). Recently, mutations in the catalytic subunit of RAB3GAP (RAB3GAP1), a key regulator of calcium-mediated hormone and neurotransmitter exocytosis, were reported in Warburg micro syndrome, a severe neurodevelopmental condition with overlapping clinical features. RAB3GAP is a heterodimeric protein that consists of a catalytic subunit and a noncatalytic subunit encoded by RAB3GAP1 and RAB3GAP2, respectively. We performed messenger RNA-expression studies of RAB3GAP1 and RAB3GAP2 orthologues in Danio rerio embryos and demonstrated that, whereas developmental expression of rab3gap1 was generalized (similar to that reported elsewhere in mice), rab3gap2 expression was restricted to the central nervous system. These findings are consistent with RAB3GAP2 having a key role in neurodevelopment and may indicate that Warburg micro and Martsolf syndromes represent a spectrum of disorders. However, we did not detect RAB3GAP2 mutations in patients with Warburg micro syndrome. These findings suggest that RAB3GAP dysregulation may result in a spectrum of phenotypes that range from Warburg micro syndrome to Martsolf syndrome.

DELINEATION OF CEREBRO-OCULO-FACIAL-SKELETAL (COFS) SYNDROME. † 478

Though initially reported as early as 1971, the Cerebro-Oculo-Facio-Skeletal (COFS) syndrome was initially delineated by Pena and Shokeir in 1974 as a progressive autosomal recessive brain and eye disorder leading to brain atrophy, hypoplasia of the corpus callosum, hypotonia, severe mental retardation, cataracts, microcornia, optic atrophy, and progressive joint contractures with postnatal growth deficiency. Even with the earliest reports, there appeared to a severe perinatal lethal form, forms similar to Cockayne syndrome, type 2, and milder forms compatible with survival through childhood. These milder conditions appear to be non-progressive and include Martsolf syndrome, CAHMR syndrome, and MICRO syndrome. Thus far, none of these entities have been associated with specific biochemical, chromosomal, or molecular defects, despite intensive investigations in many of the reported cases, and recurrence in a number of consanguineous families. We report 2 pairs of siblings who presented with classic features of COFS/MICRO syndrome, and compare them with previously reported cases and one unreported deceased case of COFS syndrome, in an effort to delineate the unique features of this phenotypic community of syndromes. This group of syndromes may represent one condition with variable interfamilial severity. Now that cellular analyses are available to test for Cockayne syndrome, we recommend that this be done in such patients. Once the genetic bases for each of these syndromes has been established, more definitive delineation may be possible.

Cataract, hypertrichosis, and mental retardation (CAHMR): A new autosomal recessive syndrome

We have studied 2 Egyptian sibs (the offspring of normal first cousins) with congenital cataract, hypertrichosis, mental retardation, and normal chromosomes. Review showed that the condition of our patients was not similar to any previously reported entity. POSSUM lists 84 syndromes with any of the above 3 main traits. Two disorders with cataract and mental retardation, Martsolf syndrome and Mollica-Pavone-Anterer syndrome, have overlapping manifestations and therefore are particularly differentiated from our cases. We suggest that the association of congenital cataract, hypertrichosis, and mental retardation observed in this report represents a new autosomal recessive syndrome.

Martsolf's syndrome in a non-Jewish boy.

Martsolf's syndrome has been described in Jewish people. We describe a patient of non-Jewish ancestry who has minor differences from other patients. The possible pattern of inheritance is discussed.