• Autosomal recessive inheritance add exclude
• Cryptorchidism add exclude
• Shawl scrotum add exclude
• Micropenis add exclude
• Hydroureter add exclude
• Hydronephrosis add exclude
• Narrow palate add exclude
• High palate add exclude
• Trigonocephaly add exclude
• Brachycephaly add exclude
• Oxycephaly add exclude
• Malar flattening add exclude
• Retrognathia add exclude
• Epicanthus add exclude
• Hypertelorism add exclude
• Hypoplasia of the maxilla add exclude
• Micrognathia add exclude
• Low-set ears add exclude
• Abnormality of the pinna add exclude
• Conductive hearing impairment add exclude
• Sensorineural hearing impairment add exclude
• Protruding ear add exclude
• Wide nasal bridge add exclude
• Anteverted nares add exclude
• Webbed neck add exclude
• Short neck add exclude
• Microcornea add exclude
• Telecanthus add exclude
• Sparse eyebrow add exclude
• Upslanted palpebral fissure add exclude
• Optic atrophy add exclude
• Pectus excavatum add exclude
• Pectus carinatum add exclude
• Precocious puberty add exclude
• Sacral dimple add exclude
• Cutis laxa add exclude
• Brachydactyly syndrome add exclude
• Postaxial hand polydactyly add exclude
• Intellectual disability add exclude
• Obesity add exclude
• Umbilical hernia add exclude
• Omphalocele add exclude
• Ventricular septal defect add exclude
• Atria septal defect add exclude
• Tetralogy of Fallot add exclude
• Pulmonic stenosis add exclude
• Patent ductus arteriosus add exclude
• Transposition of the great arteries add exclude
• Situs inversus totalis add exclude
• Polysplenia add exclude
• Talipes equinovarus add exclude
• Toe syndactyly add exclude
• Metatarsus adductus add exclude
• Preaxial foot polydactyly add exclude
• Frontal bossing add exclude
• Cerebral atrophy add exclude
• Highly arched eyebrow add exclude
• Hypoplastic nipples add exclude
• Supernumerary nipple add exclude
• Scoliosis add exclude
• Coxa valga add exclude
• Large foramen magnum add exclude
• Coxa vara add exclude
• Genu valgum add exclude
• Flared iliac wings add exclude
• Genu varum add exclude
• Shallow acetabular fossae add exclude
• External genital hypoplasia add exclude
• Spina bifida occulta add exclude
• Clinodactyly of the 5th finger add exclude
• Short stature add exclude
• Coronal craniosynostosis add exclude
• Sagittal craniosynostosis add exclude
• Lambdoidal craniosynostosis add exclude
• Preauricular pit add exclude
• Depressed nasal bridge add exclude
• Persistence of primary teeth add exclude
• Agenesis of permanent teeth add exclude
• Lateral displacement of patellae add exclude
• Wide intermamillary distance add exclude
• Aplasia/Hypoplasia of the corpus callosum add exclude
• Opacification of the corneal stroma add exclude
• Joint contracture of the hand add exclude
• Complete duplication of proximal phalanx of the thumb add exclude
• Aplasia/Hypoplasia of the middle phalanges of the hand add exclude
• Underdeveloped supraorbital ridges add exclude
• Duplication of the proximal phalanx of the hallux add exclude
• Aplasia/Hypoplasia of the middle phalanges of the toes add exclude
• Aplasia of the middle phalanx of the hand add exclude
• Pseudoepiphyses of the proximal phalanges of the hand add exclude
• Cutaneous finger syndactyly add exclude
• Broad thumb add exclude
• Midface retrusion add exclude
• Camptodactyly add exclude
• Preaxial polydactyly add exclude
• Postaxial polydactyly add exclude

CARPENTER SYNDROME 1 (CRPT1)   phenotype (molecular basis known)   201000
synopsis:

INHERITANCE:
Autosomal recessive
GROWTH:
[Height]
Short stature (<25th percentile)
[Weight]
Obesity HEAD AND NECK: [Head]
Brachycephaly
[Face]
Midface hypoplasia
[Ears]
Low-set ears
Malformed ears
Preauricular pits
Conductive hearing loss
Sensorineural hearing loss
[Eyes]
Epicanthal folds
Corneal opacity
Microcornea
Optic atrophy
Lateral displacement of medial canthi
[Nose]
Flat nasal bridge
[Mouth]
High-arched palate
[Teeth]
Missing teeth
Delayed loss of deciduous teeth
[Neck]
Short muscular neck
CARDIOVASCULAR:
[Heart]
Atrial septal defect
Ventricular septal defect
Pulmonic stenosis
Tetralogy of Fallot
[Vascular]
Transposition of great vessels
Patent ductus arteriosus
ABDOMEN:
[External features]
Umbilical hernia
Omphalocele
[Spleen]
Accessory spleens
GENITOURINARY:
[Internal genitalia, male]
Cryptorchidism
[Kidneys]
Hydronephrosis
[Ureters]
Hydroureter
SKELETAL:
[Skull]
Craniosynostosis (coronal, sagittal, lambdoid sutures)
[Spine]
Pilonidal dimple
Absent coccyx
Spina bifida occulta
Scoliosis
[Pelvis]
Coxa valga
Decreased hip-joint mobility
Flared ilia
[Limbs]
Genu valgum
Lateral displacement of patellae
[Hands]
Brachydactyly
Postaxial polydactyly
Clinodactyly
Syndactyly
Camptodactyly
[Feet]
Preaxial polydactyly
Syndactyly
Metatarsus varus
NEUROLOGIC:
[Central nervous system]
Variable delay (IQ range 52-104)
ENDOCRINE FEATURES:
Precocious puberty
MOLECULAR BASIS:
Caused by mutation in the Ras-associated protein RAB23 gene (RAB23, 606144.0001)
text:
A number sign (#) is used with this entry because of evidence that Carpenter syndrome is caused by homozygous mutation in the RAB23 gene (606144)on chromosome 6p11.
CLINICAL FEATURES
Carpenter (1909) described 2 sisters and a brother with acrocephaly, peculiar facies, brachydactyly, and syndactyly in the hands, and preaxial polydactyly and syndactyly of the toes. Temtamy (1966) could find 9 other reported cases and added one. In older patients obesity, mental retardation, and hypogonadism had been noted. In all cases the parents have been normal. Parental consanguinity was suspected in 1 case. The case of acrocephalosyndactyly with foot polydactyly reported by Owen (1952) probably represented Carpenter syndrome, as do the sibs reported by Schonenberg and Scheidhauer (1966). One patient thought to have this condition by Palacios and Schimke (1969) was 49 years old. Eaton et al. (1974) reported affected sibs. Cohen et al. (1987) described 2 affected sibs showing marked intrafamilial variability. This experience and a review of the literature suggested that the Goodman syndrome (201020) and the Summitt syndrome (272350) fall well within the clinical spectrum of the Carpenter syndrome. Gershoni-Baruch (1990) described a brother and sister with rather striking differences in severity. The first born had craniosynostosis of the sagittal suture, normal intelligence, and no abnormalities of the hands and feet. The second born sib had polysyndactyly of hands and feet, normal intelligence, and no craniosynostosis. Gershoni-Baruch (1990) suggested that polysyndactyly is not an absolute requisite for the diagnosis of Carpenter syndrome and that the Summitt and Goodman syndromes are 'within the clinical spectrum' of Carpenter syndrome, as suggested by Cohen et al. (1987). Alessandri et al. (2010) described 4 boys with Carpenter syndrome from a consanguineous Comoros Islands pedigree. All 4 boys presented with acrocephaly and polysyndactyly, but displayed variable severity of craniosynostosis ranging from cloverleaf skull to predominant involvement of the metopic ridge (turricephaly). All of the children also had a combination of brachydactyly with agenesis of the middle phalanges, syndactyly, broad thumbs, and postaxial polydactyly in the hands, with preaxial polydactyly and syndactyly of the toes. Mental development was normal in all; brain imaging showed hydrocephalus in 2 of the 4 boys. Additional features included corneal anomaly in 2, cryptorchidism in 3, umbilical hernia in 1, genu valgum in 2, umbilical hernia in 1, severe kyphoscoliosis in 1, patent ductus arteriosus in 1, and accessory spleen in 1. MAPPING Using homozygosity mapping, Jenkins et al. (2007) found linkage of Carpenter syndrome to chromosome 6p12.1-q12.
MOLECULAR GENETICS
In 15 independent families with Carpenter syndrome, Jenkins et al. (2007) identified 5 different mutations (4 truncating and 1 missense) in the RAB23 gene (see, e.g., L145X, 606144.0001; 606144.0002), which encodes a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog (HH) signaling (see 600725). In 10 patients, the disease was caused by homozygosity for the same L145X mutation that resides on a common haplotype, indicative of a founder effect in patients of northern European descent. In 4 boys with Carpenter syndrome from a consanguineous Comoros Islands pedigree, Alessandri et al. (2010) identified homozygosity for a 1-bp duplication in the RAB23 gene (606144.0003).
NOMENCLATURE
The designation of Carpenter syndrome as ACPS II is a relict of an earlier classification that made the Noack syndrome ACPS I. It is now agreed by most that Noack syndrome is the same as Pfeiffer syndrome (101600).

RAS-ASSOCIATED PROTEIN RAB23 (RAB23)   gene description   606144
text:

DESCRIPTION
Rab proteins are small GTPases of the Ras superfamily involved in the regulation of intracellular membrane trafficking. The RAB23 gene encodes an essential negative regulator of the Sonic hedgehog (SHH; 600725) signaling pathway. For additional background information on Rab proteins, see 179508. CLONING By a map-based approach, Eggenschwiler et al. (2001) cloned the gene mutant in the mouse 'open brain 'phenotype (opb; see later) and found that it encodes Rab23, a member of the Rab family of vesicle transport proteins. The human RAB23 gene encodes a 237-amino acid protein. RAB23 is 30 to 35% identical to other mammalian Rab proteins and includes all the canonical motifs required for guanine nucleotide binding, GTP hydrolysis, membrane association, and the conformational switch between the GTP and GDP-bound state. Rab23 is a relatively divergent Rab protein with an unusually long carboxy-terminal tail. In the mouse at embryonic day 10.5, Rab23 RNA was present at low levels in most tissues, and was present at high levels in the spinal cord, somites, limb buds, and cranial mesenchyme. In the spinal cord, Rab23 was expressed at highest levels in the dorsal half of the neural tube, although it was excluded from the roof plate. In the limb bud, it was expressed in the crescent of mesenchymal cells that are capable of responding to Shh signaling. The expression pattern of Rab23 RNA is similar to that of Gli3 (165240), another negative regulator of the Shh signaling pathway.
GENE STRUCTURE
The RAB23 gene contains 8 exons, and the first 2 exons are noncoding (Alessandri et al., 2010). MAPPING By database searching, Zhang et al. (2000) mapped the RAB23 gene to chromosome 6p11 based on similarity between the RAB23 sequence (GenBank
GENBANK AF
161486) and previously mapped sequences.
GENE FUNCTION
Mutations in Shh and opb cause opposing transformations in neural cell fate: Shh mutant embryos lack ventral cell types throughout the spinal cord, whereas opb mutant embryos lack dorsal cell types specifically in the caudal spinal cord. Eggenschwiler et al. (2001) demonstrated that opb acts downstream of Shh. Ventral cell types that are absent in Shh mutants, including the floor plate, are present in Shh-opb double mutants. The organization of ventral cell types in Shh-opb double mutants reveals that Shh-independent mechanisms can pattern the neural tube along its dorsal-ventral axis. Eggenschwiler et al. (2001) concluded that dorsalizing signals activate transcription of Rab23 in order to silence the Shh pathway in dorsal neural cells.
MOLECULAR GENETICS
Carpenter syndrome (201000) is a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects. In 15 independent families with Carpenter syndrome, Jenkins et al. (2007) identified 5 different mutations, including 4 truncating (see, e.g., L145X, 606144.0001; 606144.0002) and 1 missense, in the RAB23 gene. In 10 patients, the disease was caused by homozygosity for the same L145X mutation that resides on a common haplotype, indicative of a founder effect in patients of northern European descent. Nonsense mutations of Rab23 in 'open brain' mice were found to cause recessive embryonic lethality with neural tube defects, suggesting a species difference in the requirement for RAB23 during early development. The discovery of RAB23 mutations in patients with Carpenter syndrome implicated HH signaling in cranial suture biogenesis; this was an unexpected finding given that craniosynostosis is not usually associated with mutations of other HH pathway components. The finding also provides a new molecular target for studies of obesity, which is a consistent feature of Carpenter syndrome. In a consanguineous Comoros Islands pedigree with Carpenter syndrome, Alessandri et al. (2010) identified homozygosity for a 1-bp duplication in the RAB23 gene (606144.0003).
ANIMAL MODEL
Homozygous 'open brain' (opb) mice die during the second half of gestation, with an open neural tube in the head and spinal cord, abnormal somites, polydactyly, and poorly developed eyes (Gunther et al., 1994). Eggenschwiler et al. (2001) found that the opb mutation arises from the Rab23 gene. The opb1 allele encodes a lys-to-ter mutation at codon 39; the opb2 allele encodes an arg-to-ter mutation at codon 80. These alleles would lack the domains required for guanine nucleotide and Rab effector binding and are therefore null alleles.

BTRC (textmining 430)	CD74 (textmining 484)	CSNK1G2 (textmining 635)	DAB2 (textmining 491)
EFNB1 (textmining 473)	FANCB (textmining 413)	FGFR2 (textmining 483)	FGFR4 (textmining 446)
FKBP8 (textmining 559)	GLI1 (textmining 937)	GLI2 (textmining 456)	HIP1 (textmining 517)
LRP2 (textmining 405)	MLPH (textmining 514)	MSX2 (textmining 418)	MT1X (textmining 567)
NKX2-2 (textmining 479)	OR6C1 (textmining 671)	PAX7 (textmining 429)	PTCH1 (textmining 690)
RTDR1 (textmining 583)	SAP18 (textmining 601)	SHD (textmining 627)	SHH (textmining 818)
SLC6A1 (textmining 418)	SMO (textmining 819)	SRMS (textmining 470)	SUFU (textmining 539)
SYTL1 (textmining 659)	SYTL5 (textmining 627)	TOP2A (textmining 502)	TP53I3 (textmining 623)
TULP3 (textmining 617)

• autophagosome assembly
• GTPase activity
• protein binding
• GTP binding
• cytoplasm
• autophagosome
• centrosome
• cytosol
• plasma membrane
• intracellular protein transport
• cellular defense response
• endosome membrane
• endomembrane system
• cell junction
• phagocytic vesicle membrane
• negative regulation of protein import into nucleus
• phagocytic vesicle
• GTP metabolic process
• cilium assembly
• craniofacial suture morphogenesis

PRIMASE POLYPEPTIDE 2A (PRIM2A)   gene description   176636
text:

DESCRIPTION
DNA replication in human cells is initiated by a complex apparatus containing a DNA polymerase-alpha/primase complex that is well conserved from yeast to human. The DNA polymerase-alpha/primase complex contains 4 subunits: the polymerase-alpha p180 (POLA; 312040) and p68 (POLA2) subunits, and the primase p58 (PRIM2A) and p49 (PRIM1; 176635) subunits. Primase synthesizes oligoribonucleotides that serve as primers for the initiation of DNA synthesis. It plays a role in both the initiation of DNA replication and the synthesis of Okazaki fragments for lagging strand synthesis (Shiratori et al., 1995). CLONING By RT-PCR of embryonic kidney cell line RNA using degenerate primers based on mouse and yeast primase subunits, followed by 5-prime RACE, Stadlbauer et al. (1994) cloned the primase p58 subunit. The deduced 446-amino acid protein shares 89% identity with mouse p58, with 5 regions of homology distributed over the central part of the protein. The N and C termini are less well conserved.
GENE FUNCTION
Stadlbauer et al. (1994) demonstrated that mouse and human p58 showed no primase activity in the absence of p48. Zerbe and Kuchta (2002) found that deletion of met288 to leu313 within the polymerase-beta (174760)-like domain of human p58 resulted in a protein that bound to the primase p49 subunit but was unable to support primer synthesis on any template when assays contained only Mg(2+). Including Mn(2+), a metal that stimulates initiation of primer synthesis, allowed the p49/p58 primase complex to synthesize primers at a rate only moderately lower than that of the wildtype enzyme on templates consisting only of deoxycytidylates. By point mutagenesis, Zerbe and Kuchta (2002) determined that arg302, arg306, and lys314 were required for both primer initiation and translocation. Conversion of these residues to alanine interfered with initiation and significantly decreased the processivity of primase. Zerbe and Kuchta (2002) concluded that the polymerase-beta-like region of p58 is important for primer initiation, translocation, and counting. MAPPING By PCR amplification using DNAs from a panel of somatic cell hybrids, Shiratori et al. (1995) mapped the PRIM1 gene and the PRIM2 gene to chromosomes 1 and 6, respectively. By fluorescence in situ hybridization using several genomic DNA probes, they mapped the PRIM1 gene to 1q44 and two PRIM2 loci (PRIM2A and PRIM2B) to 6p12-p11.1. In an erratum to Shiratori et al. (1995), the authors stated that the gene on 1q44 was in fact a processed PRIM1 pseudogene (PRIM1P). The PRIM2B locus identified by Shiratori et al. (1995) may also be a pseudogene (Scott, 2004).

APEX1 (textmining 480)	BRCA2 (textmining 432)	CRY1 (textmining 554)	DNA2 binding (reactome 900)
ERCC1 (textmining 522)	FEN1 catalysis (reactome 900)	FOXN3 (textmining 653)	LMAN1 (textmining 469)
ORC1 (textmining 647)	POLA1 binding,reaction,catalysis (grid,reactome,kegg_pathways,intact 995)	POLA2 (textmining,experimental 998)	POLB (textmining 492)
POLD1 binding (kegg_pathways 978)	POLD3 (textmining 747)	PRIM1 binding,reaction,catalysis (grid,reactome,kegg_pathways,bind,intact 994)	PRKDC (textmining 581)
RBMS1 (textmining 609)	RECQL (textmining,experimental 627)	RRBP1 (textmining 434)	SET (textmining 513)
SRFBP1 (textmining 935)	SRPR binding (kegg_pathways,intact 419)	SUPT16H (textmining 427)	XRCC6 (textmining 530)

TRANSLOCATION-ASSOCIATED MEMBRANE PROTEIN 2 (TRAM2)   gene description   608485
text:

DESCRIPTION
TRAM2 is a component of the translocon, a gated macromolecular channel that controls the posttranslational processing of nascent secretory and membrane proteins at the endoplasmic reticulum (ER) membrane. CLONING By sequencing clones obtained from a size-fractionated myeloid cell line cDNA library, Nomura et al. (1994) cloned TRAM2, which they designated KIAA0057. The 3-prime untranslated region of the transcript contains an Alu repeat. The deduced 370-amino acid protein contains possible transmembrane domains. TRAM2 shares 51.6% identity with human RA-regulated nuclear matrix associated protein, RAMP (602221). Northern blot analysis detected moderate expression in all tissues examined except brain. Using the sequence of KIAA0057 to design primers, Onuchic et al. (1999) amplified TRAM2 from kidney cDNA. TRAM2 shares 68% homology with TRAM1 (605190). Northern blot analysis detected 7.0-kb and 0.8-kb TRAM2 transcripts in fetal lung, liver, and kidney. Only the 0.8-kb transcript was detected in fetal brain. Stefanovic et al.(2004) cloned human and rat TRAM2 by differential display of activated and quiescent hepatic stellate cells. The deduced protein contains 7 putative transmembrane regions and shows the same topology as that predicted for TRAM1, but TRAM2 differs at the C terminus.
GENE FUNCTION
Upon activation, quiescent hepatic stellate cells proliferate, change morphologically into myofibroblasts, and increase their synthesis of extracellular matrix proteins. Stefanovic et al. (2004) demonstrated that both TRAM2 and collagen type I (see 120150) are upregulated in activated rat and human hepatic stellate cells. By yeast 2-hybrid screen and in vitro binding assays, they further found that the C terminus of TRAM2 interacts with SERCA2b (108740), the main Ca(2+) pump in the endoplasmic reticulum of hepatic stellate cells and fibroblasts. TRAM2 also coprecipitated with collagen. Deletion of the C terminus of TRAM2, and pharmacologic inhibitors of SERCA2b, inhibited type I collagen synthesis. In addition, depletion of ER Ca(2+) inhibited the folding of triple helical collagen and increased its intracellular degradation. Stefanovic et al. (2004) proposed that, during activation of hepatic stellate cells, TRAM2 recruits SERCA2b to the translocon, and SERCA2b then couples procollagen synthesis and Ca(2+)-dependent molecular chaperones involved in collagen folding.
GENE STRUCTURE
Onuchic et al. (1999) determined that the TRAM2 gene contains 11 exons and spans 79.6 kb. MAPPING By PCR of a human/rodent hybrid panel, Nomura et al. (1994) mapped the TRAM2 gene to chromosome 6. By genomic sequence analysis, Onuchic et al. (1999) mapped the TRAM2 gene to chromosome 6p21.1-p12 near the PKHD1 (606702) gene.

ADM2 (textmining 546)	ATP2A1 (textmining 496)	ATP2A2 (textmining 446)	ATP2A3 (textmining 645)
ATP2B1 (textmining 524)	COL1A1 (textmining 630)	CRISP1 (textmining 601)	EFHC1 (textmining 716)
ELOVL5 (textmining 631)	FBXO9 (textmining 679)	GCLC (textmining 595)	GCM1 (textmining 593)
GSTA3 (textmining 609)	GSTA4 (textmining 597)	GTF2B (experimental 611)	IAPP (textmining 414)
IL17F (textmining 420)	LRRC1 (textmining 710)	MCM3 (textmining 667)	MTSS1 (textmining 434)
PAQR8 (textmining 667)	PGK2 (textmining 581)	PKHD1 (textmining 839)	PLN (textmining 474)
POLR2A (experimental 611)	RAB27A (textmining 425)	RHAG (textmining 530)	RUNX2 (textmining 872)
SLC8A1 (textmining 583)	TBP (experimental 611)	TFAP2B (textmining 613)	TMEM14A (textmining 688)
TNFRSF12A (textmining 577)	WTAP (textmining 643)

LEUCINE-RICH REPEAT-CONTAINING PROTEIN 1 (LRRC1)   gene description   608195
text:
CLONING By searching an EST database for sequences similar to scribble (607733) and erbin (606944), followed by RACE of breast mRNA, Saito et al. (2001) cloned LRRC1, which they designated LANO. The deduced protein contains 16 leucine-rich repeats and a LAP-specific domain, but no PDZ domain. LRRC1 shares 60%, 42%, and 40% amino acid identity with scribble, rat densin-180, and erbin, respectively. Northern blot analysis detected a 3.5-kb transcript expressed predominantly in placenta, kidney, pancreas, prostate, testis, colon, thyroid, and adrenergic glands. Western blot analysis detected endogenous LRRC1 at an apparent molecular mass of about 62 kD in a human colon epithelial (Caco2) cell line. Immunolocalization and confocal sections of permeabilized Caco2 cells detected LRRC1 expression on the basolateral surface.
GENE FUNCTION
By in vitro and in vivo pull-down assays with transfected Caco2 cells, Saito et al. (2001) demonstrated that LRRC1 and a C-terminal LRRC1 peptide interacted with the PDZ domains of DLG1 (601014) and PSD95 (DLG4; 602887). They found a second pool of LRRC1 in a complex with erbin. MAPPING Saito et al. (2001) stated that the LRRC1 gene maps to chromosome 6p12.3-p12.2.

DLG1 binding (NLP,mint 599)	DLG4 (fusion,textmining,experimental 599)	EFHC1 (textmining 692)	ELOVL5 (textmining 641)
FBXO9 (textmining 683)	GCLC (textmining 611)	GCM1 (textmining 605)	GSTA3 (textmining 619)
GSTA4 (textmining 609)	GUK1 (textmining 512)	IL17F (textmining 446)	MCM3 (textmining 581)
MTSS1 (textmining 460)	PAQR8 (textmining 673)	PKHD1 (textmining 554)	SSB (textmining 408)
TFAP2B (textmining 625)	TMEM14A (textmining 690)	TRAM2 (textmining 710)	WTAP (textmining 651)